Anticancer compounds

ABSTRACT

The invention provides compounds having the general formula I: 
                         
and salts thereof, wherein the variables R A , R B , R C , L 1 , L 2 , L 3 , A, B, C, X, Y, Z, E, m, n, and p have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/394,050, filed 13 Sep. 2016. The entire content of U.S. Provisional Application No. 62/394,050 is hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in the United States with estimated 48,960 new cases and 40,560 deaths in 2015 (Siegel, R. L. et al. CA. Cancer J. Clin. 2015, 65, 5-29). With a five-year overall survival rate of merely 7 percent, PDAC is the most lethal cancer among major malignancies. Its poor prognosis is partly due to the fact that PDAC is usually diagnosed at advanced stages. Moreover, pancreatic cancer cells acquire a large number of genetic mutations and are notoriously resistant to apoptotic cell death, an established cancer cell-killing mechanism elicited by anti-cancer agents (Jones, S. et al. Science 2008, 321, 1801-1806; and Hezel, A. F. et al. Genes Dev. 2006, 20, 1218-1249). Despite numerous efforts, there still is a dire lack of effective therapeutic options for advanced pancreatic cancer (Garrido-Laguna, I. et al. Nat. Rev. Clin. Oncol. 2015, 12, 319-334; and Spadi, R. et al. World J. Clin. Oncol. 2016, 7, 27-43). Modulation of macroautophagy (hereafter referred to as autophagy) has been proposed as a promising strategy (Gomez, V. E. et al. Semin. Cancer Biol. 2015, 35, 11-19).

Autophagy is a conserved cellular process through which cytosolic components, such as proteins and organelles, are sequestered, degraded, and recycled (He, C. et al. Annu. Rev. Genet. 2009, 43, 67-93; and Choi, A. M. et al. N. Engl. J. Med. 2013, 368, 651-662). The precise roles of autophagy in tumorigenesis and cancer therapy still remain to be defined due to the heterogeneous nature of cancers and the complexity of the autophagy machinery (Galluzzi, L. et al. EMBO J. 2015, 34, 856-880). Studies have shown that autophagy plays different or even opposite roles depending on the cancer type and the stage of tumor progression. Currently, it is generally accepted that autophagy behaves as a tumor suppressor in normal cells in part because it removes damaged cellular components. Nevertheless, increasing evidence shows that autophagy is a cytoprotective mechanism often exploited by established cancer cells to cope with their harsh microenvironment and cellular stresses induced by chemotherapies. A number of anticancer agents with diverse mechanisms of action have been shown to induce autophagy (Sui, X. et al. Cell Death Dis. 2013, 4, e838; and Dong, Z. et al. Blood Rev. 2016, doi: 10.1016/j.blre.2016.04.005). More importantly, autophagy inhibitors enhance the efficacy of many anticancer agents (Sui, X. et al. Cell Death Dis. 2013, 4, e838). For pancreatic cancer, it has been shown that autophagy is elevated and required for de novo tumor growth and inhibition of autophagy leads to robust tumor regression (Fujii, S. et al. Cancer Sci. 2008, 99, 1813-1819; and Yang, S. et al. Genes Dev. 2011, 25, 717-729); however, the status of p53, whose mutation is commonly seen in pancreatic cancer patients, may determine the outcome of autophagy inhibition (Rosenfeldt, M. T. et al. Nature 2013, 504, 296-300; and Yang, A. et al. Cancer Discov. 2014, 4, 905-913). Despite the complexity of autophagy inhibition as a therapeutic strategy, these studies suggest that disabling the pro-survival autophagy machinery hijacked by cancer cells might represent a viable approach to promote cell death and reduce drug resistance in refractory cancers such as pancreatic cancer (Gomez, V. E. et al. Semin. Cancer Biol. 2015, 35, 11-19; and Sui, X. et al. Cell Death Dis. 2013, 4, e838).

Therefore, there is a need for new compounds to treat cancer, especially pancreatic cancer.

SUMMARY OF THE INVENTION

The invention provides compounds that treat cancer, especially pancreatic cancer.

Accordingly, the invention provides a compound of formula I:

wherein:

ring A is aryl or heteroaryl;

ring B is aryl, heteroaryl, carbocycle or heterocycle;

ring C is aryl or heteroaryl;

L¹ is C₁₋₄ alkylene, -L^(A)-O-L^(B)-, -L^(A)-S-L^(B), L^(A)-NR¹-L^(B)-, -L^(A)-NR¹C(O)-L^(B)-, -L^(A)-NR¹SO₂-L^(B)-, -L^(A)-C(O)NR¹-L^(B)-, or -L^(A)-SO₂NR¹-L^(B)-; wherein each R¹ is independently hydrogen or C₁₋₄ alkyl; each L^(A) is independently absent or C₁₋₄ alkylene; each L^(B) is independently absent or C₁₋₄ alkylene;

L² is C₁₋₄ alkylene, -L^(C)-O-L^(D)-, -L^(C)-S-L^(D), L^(C)-NR²-L^(D)-, -L^(C)-NR²C(O)-L^(D)-, or -L^(C)-C(O)NR²-L^(D)-; wherein each R² is independently hydrogen or C₁₋₄ alkyl; each L^(C) is independently absent or C₁₋₄ alkylene; each L^(D) is independently absent or C₁₋₄ alkylene;

L³ is C₁₋₄ alkylene, -L^(E)-O-L^(F)-, -L^(E)-S-L^(F), -L^(E)-NR¹¹-L^(F)-, -L^(E)-NR¹¹C(O)-L^(F)-, or -L^(E)-C(O)NR¹¹-L^(F)-; wherein each R¹¹ is independently hydrogen or C₁₋₄ alkyl; each L^(E) is independently absent or C₁₋₄ alkylene; each L^(F) is independently absent or C₁₋₄ alkylene;

X is N or C—R^(X); wherein R^(X) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR³, —SR³, —N(R³)₂, —NO₂ or —CN; wherein each R³ is independently hydrogen or C₁₋₄ alkyl;

Y is N or C—R^(Y); wherein R^(Y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁴, —SR⁴, —N(R⁴)₂, —NO₂ or —CN; wherein each R⁴ is independently hydrogen or C₁₋₄ alkyl;

Z is N or C—R^(Z); wherein R^(Z) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁵, —SR⁵, —N(R⁵)₂, —NO₂ or —CN; wherein each R⁵ is independently hydrogen or C₁₋₄ alkyl;

E is N or C—R^(E); wherein R^(E) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁶, —SR⁶, —N(R⁶)₂, —NO₂ or —CN; wherein each R⁶ is independently hydrogen or C₁₋₄ alkyl;

each R^(A) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁷, —SR⁷, —N(R⁷)₂, —NO₂ or —CN; wherein each R⁷ is independently hydrogen or C₁₋₄ alkyl;

each R^(B) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁸, —SR⁸, —N(R⁸)₂, —NO₂ or —CN; wherein each R⁸ is independently hydrogen or C₁₋₄ alkyl;

each R^(C) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁹, —SR⁹, —N(R⁹)₂, —NO₂, —CN, —C(O)N(R⁹)₂ or —NR⁹C(O)R¹⁰; wherein each R⁹ is independently hydrogen, C₁₋₄ alkyl or aryl; R¹⁰ is C₁₋₄ alkyl or aryl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4;

provided that at least one of X, Y, Z and E is N;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for treating cancer in an animal (e.g., a mammal, such as a human) comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.

DETAILED DESCRIPTION

The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C₁₋₄ means one to four carbons). Non limiting examples of “alkyl” include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane (including straight and branched alkanes), as exemplified by —CH₂CH₂CH₂CH₂— and —CH(CH₃)CH₂CH₂—.

The term “halo” means fluoro, chloro, bromo, or iodo.

The term “haloalkyl” means an alkyl that is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halo. Non limiting examples of “haloalkyl” include iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl 2,2-difluoroethyl and pentafluoroethyl.

The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic. Such multiple condensed ring systems may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aryl or a carbocycle portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a 3-6 membered single aromatic ring that has at least one (e.g., 1, 2, 3 or 4) atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes 7-20 membered multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

The term “carbocycle” refers to a single saturated (i.e., cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms (i.e. (C₃-C₇)carbocycle). The term “carbocycle” also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles having 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc), via two adjacent carbon atoms to form a fused connection such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g. norbornane, bicyclo[2.2.2]octane, etc). The “carbocycle” may also be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl and cycloheptyl.

The term “heterocycle” refers to a saturated or partially unsaturated ring system radical having the overall having from 3-20 ring atoms that contain from one to ten heteroatoms selected from N, O, and S. Unless otherwise stated, a “heterocycle” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. Non limiting examples of “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like. A “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.

The terms “treat” and “treatment” refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

The phrase “effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

In one embodiment, the compound is a compound of formula Ia:

wherein G is N or CH;

m is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound of formula Ib:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound of formula Ic:

wherein G is N or CH;

m is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

In one embodiment, R^(Z) is C₁₋₄ alkyl.

In one embodiment, R^(Z) is methyl.

In one embodiment, R^(E) is C₁₋₄ alkyl.

In one embodiment, R^(E) is methyl.

In one embodiment, m is 0.

In one embodiment, ring B is phenyl, pyridyl, cyclohexyl or naphthalenyl.

In one embodiment, each R^(B) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁸, —NO₂ or CN; wherein R⁸ is hydrogen or C₁₋₄ alkyl.

In one embodiment, each R^(B) is independently CH₃, —OCH₃, —Cl, —CN, —NO₂, or CF₃.

In one embodiment, n is 0, 1, or 2.

In one embodiment, the group

is selected from the group consisting of:

In one embodiment, ring C is phenyl or pyridyl.

In one embodiment, each R^(C) is independently —N(R⁹)₂, —NO₂, —C(O)N(R⁹)₂ or —NR⁹C(O)R¹⁰; wherein each R⁹ is independently hydrogen, C₁₋₄ alkyl or aryl; R¹⁰ is C₁₋₄ alkyl or aryl.

In one embodiment, each R^(C) is independently C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —C(O)NHEt, —C(O)NH^(i)Pr, —C(O)NHPh, —NO₂, —NH₂, or —NHC(O)Me.

In one embodiment, p is 0 or 1.

In one embodiment, the group

is selected from the group consisting of:

In one embodiment, L¹ is -L^(A)-NR¹-L^(B)-, -L^(A)-NR¹C(O)-L^(B)-, or -L^(A)-NR¹SO₂-L^(B)-; wherein each R¹ is independently hydrogen or C₁₋₄ alkyl; each L^(A) is independently absent or C₁₋₄ alkylene; each L^(B) is independently absent or C₁₋₄ alkylene.

In one embodiment, L¹ is —NMeC(O)—, —NHC(O)—, —NHCH₂—, or —NHSO₂—.

In one embodiment, L¹ is —NHC(O)—.

In one embodiment, L² is C₁₋₄ alkylene, -L^(C)-NR²-L^(D)-, -L^(C)-O-L^(D)-, -L^(C)-S-L^(D), or -L^(C)-(CO)NR²-L^(D)-; wherein each R² is independently hydrogen or C₁₋₄ alkyl; each L^(C) is independently absent or C₁₋₄ alkylene; each L^(D) is independently absent or C₁₋₄ alkylene.

In one embodiment, L² is —CH₂O—, —CH(CH₃)O—, —CH₂S—, —CH₂NH—, —CH₂CH₂—, —(CO)NH—, —OCH₂—, or —O—.

In one embodiment, L² is —CH₂O—.

In one embodiment, L³ is C₁₋₄ alkylene.

In one embodiment, L³ is —CH₂— or —CH(CH₃)—.

In one embodiment, the invention provides a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the cancer is selected from pancreatic cancer, bile duct carcinoma, neuroblastoma, colon cancer, breast cancer, myeloma, gastric cancer, liver cancer, glioblastoma, ovarian cancer, colorectal cancer, non-Hodgkin lymphoma, lung cancer, prostate cancer, small-cell lung cancer, large cell lung cancer, kidney cancer, esophageal cancer, stomach cancer, cervical cancer or lymphoma tumors.

In one embodiment, the cancer is pancreatic cancer.

The invention also provides a method for inhibiting cancer cell growth in an animal comprising administering an inhibitory effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, to the animal.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic inhibition of cancer cell growth.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the inhibition of cancer cell growth.

In one embodiment, the cancer cell is pancreatic cancer cell.

Processes and intermediates useful for preparing compounds of formula I are provided as further embodiments of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.

Compounds of formula I may be prepared by the process illustrated in Schemes 1-8.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES Example 1 Synthesis of N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A1) Step 1. Synthesis of 1-Benzyl-3,5-dimethyl-1H-pyrazol-4-amine (IA3a)

To a solution of 3,5-dimethyl-4-nitropyrazole (IA1, 1.41 g, 10 mmol) in DMF (30 mL) were added benzyl bromide (IA2a, 2.05 g, 12 mmol) and Cs₂CO₃ (6.52 g, 20 mmol) and the mixture was allowed to stir at rt for 24 h. The reaction was quenched with water (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. After purification by flash column chromatography (0-50% EtOAc/hexanes), 1-benzyl-3,5-dimethyl-4-nitro-1H-pyrazole was obtained as a white solid (1.39 g, 60%). ¹H NMR (CDCl₃, 600 MHz) δ 7.37-7.28 (m, 3H), 7.16-7.12 (m, 2H), 5.26 (s, 2H), 2.56 (s, 3H), 2.55 (s, 3H). HRMS (ESI⁺) calcd for C₁₂H₁₄N₃O₂ (M+H)⁺ 232.1081, found 232.1079.

This nitro compound (1.39 g, 6.0 mmol) and NiCl₂.6H₂O (2.85 g, 12 mmol) were then dissolved in MeOH (70 mL). NaBH₄ (907 mg, 24 mmol) was slowly added to the above solution and the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K₂CO₃, and concentrated in vacuo. The residue was purified by flash column chromatography (0-60% EtOAc/hexanes) to afford compound IA3a as a brown oil (1.00 g, 50% over two steps). ¹H NMR (CDCl₃, 600 MHz) δ 7.32-7.25 (m, 2H), 7.24-7.20 (m, 1H), 7.07-7.03 (m, 2H), 5.16 (s, 2H), 2.20 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) C₁₂H₁₆N₃ (M+H)⁺ 202.1339, found 202.1342.

Step 2. Synthesis of N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A1)

To a solution of 4-(phenoxymethyl)-benzoic acid (55 mg, 0.24 mmol) and EDC (46 mg, 0.24 mmol) in DMF/CH₂Cl₂ (1:1, 10 mL) was added amine IA3a (40 mg, 0.20 mmol) and the mixture was allowed to stir at rt for 12 h. After the solvents were removed, the residue was diluted with EtOAc (30 mL), H₂O (10 mL) and saturated NaHCO₃ (10 mL). After separation, the organic layer was washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography (0-10% MeOH/CH₂Cl₂) to give compound A1 as a white solid (85 mg, 90%). ¹H NMR (CDCl₃, 600 MHz) δ 7.90 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.2 Hz, 2H), 7.33-7.27 (m, 4H), 7.27-7.21 (m, 2H), 7.12 (d, J=7.8 Hz, 2H), 7.00-6.95 (m, 3H), 5.23 (s, 2H), 5.15 (s, 2H), 2.21 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) C₂₆H₂₆N₃O₂ (M+H)⁺ 412.2020, found 412.2022.

Example 2 Synthesis of N-(1-(4-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A2a) Step 1. Synthesis of Methyl 4-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoate (IA3b)

Intermediate IA3b was prepared with bromide IA2b, in a fashion similar to the one described for intermediate IA3a. Brown oil, 788 mg, 91% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.96 (d, J=7.8 Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 5.21 (s, 2H), 3.9 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₈N₃O₂ (M+H)⁺ 260.1394, found 260.1395.

Step 2. Synthesis of Methyl 4-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoate (IA4a)

Compound IA4a was prepared from IA3b, via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. White solid, 300 mg, 64% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.56 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.88 (d, J=7.8 Hz, 1H), 7.83 (s, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.51 (dd, J=7.5, 7.5 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.32 (s, 2H), 5.20 (s, 2H), 3.85 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₃O₄ (M+H)⁺ 470.2080, found 470.2083.

Step 3. Synthesis of N-(1-(4-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A2a)

A solution of methyl ester IA4a (47 mg, 0.10 mmol) in NH₃/MeOH (˜7 N, 5 mL) in a sealed tube was heated at 70° C. for 16 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-20% MeOH/CH₂Cl₂) to afford compound A2a as a white solid (14 mg, 31%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.55 (s, 1H), 7.97 (d, J=7.8 Hz, 2H), 7.92 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.34 (s, 1H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.29 (s, 2H), 5.20 (s, 2H), 2.06 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₇N₄O₃ (M+H)⁺ 455.2083, found 455.2087.

Example 3 Synthesis of N-(1-(3-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A2b) Step 1. Synthesis of Methyl 3-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoate (IA3c)

Intermediate IA3c was prepared with bromide IA2c, in a fashion similar to the one described for intermediate IA3a. Brown oil, 683 mg, 81% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.92 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 5.20 (s, 2H), 3.90 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₈N₃O₂ (M+H)⁺ 260.1394, found 260.1394.

Step 2. Synthesis of Methyl 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoate (IA4b)

Compound IA4b was prepared from IA3c, via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. White solid, 200 mg, 40% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.40 (dd, J=7.5, 7.5 Hz, 1H), 7.32-7.28 (m, 3H), 7.24-7.20 (m, 1H), 7.00-6.95 (m, 3H), 5.27 (s, 2H), 5.15 (s, 2H), 3.91 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₃O₄ (M+H)⁺ 470.2080, found 470.2075.

Step 3. Synthesis N-(1-(3-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-phenoxymethyl)benzamide (A2b)

Compound A2b was prepared from IA4b, in a fashion similar to the one described for compound A2a. White solid, 23 mg, 50% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.56 (s, 1H), 8.01-7.94 (m, 3H), 7.77 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.42 (dd, J=7.5, 7.5 Hz, 1H), 7.38 (s, 1H), 7.30 (dd, J=7.5, 7.5 Hz, 2H), 7.26 (d, J=7.8 Hz, 1H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.27 (s, 2H), 5.20 (s, 2H), 2.08 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₇N₄O₃ (M+H)⁺ 455.2083, found 455.2082.

Example 4 Synthesis of N-(1-(2-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A2c) Step 1. Synthesis of Methyl 2-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoate (IA3d)

Compound IA3d was prepared with bromide IA2d, in a fashion similar to the one described for intermediate IA3a. Brown oil, 776 mg, 89% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.00 (d, J=8.4 Hz, 1H), 7.38 (dd, J=7.2, 7.2 Hz, 1H), 7.29 (dd, J=7.8, 7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 5.61 (s, 2H), 3.93 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₈N₃O₂ (M+H)⁺ 260.1394, found 260.1396.

Step 2. Synthesis of Methyl 2-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoate (IA4c)

Compound IA4c was prepared from IA3d, in a fashion similar to the one described for compound A1. White solid, 776 mg, 89% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.61 (s, 1H), 7.99 (d, J=7.8 Hz, 2H), 7.93 (d, J=7.2 Hz, 1H), 7.60-7.52 (m, 3H), 7.42 (dd, J=7.2, 7.2 Hz, 1H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 5.58 (s, 2H), 5.20 (s, 2H), 3.89 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₃O₄ (M+H)⁺ 470.2080, found 470.2081.

Step 3. Synthesis of N-(1-(2-Carbamoylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A2c)

Compound A2c was prepared from IA4c, in a fashion similar to the one described for compound A2a. White solid, 13 mg, 29% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.58 (s, 1H), 8.04 (s, 1H), 7.98 (d, J=7.8 Hz, 2H), 7.57 (d, J=7.8 Hz, 2H), 7.55-7.50 (m, 2H), 7.38 (dd, J=7.5, 7.5 Hz, 1H), 7.35-7.27 (m, 3H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 5.41 (s, 2H), 5.20 (s, 2H), 2.04 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₇N₄O₃ (M+H)⁺ 455.2083, found 455.2081.

Example 5 Synthesis of N-(3,5-Dimethyl-1-(4-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A3a)

A solution of methyl ester IA4a (47 mg, 0.10 mmol) in MeNH₂/EtOH (33 wt. %, 7 mL) in a sealed tube was heated at 70° C. for 24 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-20% MeOH/CH₂Cl₂) to afford compound A3a as a white solid (32 mg, 68%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.55 (s, 1H), 8.41-8.35 (m, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.29 (s, 2H), 5.20 (s, 2H), 2.77 (d, J=4.8 Hz, 3H), 2.06 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃(M+H)⁺ 469.2240, found 469.2241.

Example 6 Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (A3b)

Compound A3b was prepared from IA4b, in a fashion similar to the one described for compound A3a. White solid, 30 mg, 64% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.56 (s, 1H), 8.47-8.40 (m, 1H), 7.97 (d, J=7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.43 (dd, J=7.4, 7.4 Hz, 1H), 7.33-7.24 (m, 3H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.28 (s, 2H), 5.20 (s, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.07 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃(M+H)⁺ 469.2240, found 469.2240.

Example 7 Synthesis of 2-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (A3c)

Compound A3c was prepared from IA4c, in a fashion similar to the one described for compound A3a. White solid, 13 mg, 28% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.57 (s, 1H), 8.50-8.44 (m, 1H), 7.98 (d, J=7.8 Hz, 2H), 7.57 (d, J=7.8 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 7.39 (dd, J=7.5, 7.5 Hz, 1H), 7.36-7.26 (m, 3H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 5.37 (s, 2H), 5.20 (s, 2H), 2.80 (d, J=3.6 Hz, 3H), 2.03 (s, 6H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃ (M+H)⁺ 469.2240, found 469.2237.

Example 8 Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N,N-dimethylbenzamide (A4a) Step 1. Synthesis of 4-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoic Acid (IA5a)

To a solution of methyl ester IA4a (40 mg, 0.086 mmol) in H₂O/MeOH (1:1, 20 mL) was added NaOH (7 mg, 0.17 mmol) and the mixture was allowed to stir at rt for 12 h. After the MeOH was evaporated in vacuo, the residue was acidified with 1N HCl to pH=2 and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to afford compound IA5a as a white solid (19 mg, 49%). ¹H NMR (DMSO-d₆, 600 MHz) δ 12.93 (s, 1H), 9.56 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.92 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.32 (s, 2H), 5.20 (s, 2H), 2.06 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₆N₃O₄ (M+H)⁺456.1923, found 456.1924.

Step 2. Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoic Acid (IA5b)

Compounds IA5b was prepared from IA4b, in a fashion similar to the one described for compound IA5a. White solid, 23 mg, 59% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ13.01 (s, 1H), 9.56 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.85 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.49 (dd, J=7.5, 7.5 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.30 (dd, J=7.5, 7.5 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 2.07 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₆N₃O₄ (M+H)⁺ 456.1923, found 456.1925.

Step 3. Synthesis of 2-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)benzoic Acid (IA5c)

Compounds IA5c was prepared from IA4c, in a fashion similar to the one described for compound IA5a. White solid, 17 mg, 43% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.61 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.50 (dd, J=8.8, 7.8 Hz, 1H), 7.39 (dd, J=7.5, 7.5 Hz, 1H), 7.30 (dd, J=7.8, 7.8 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.5, 7.5 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H), 5.60 (s, 2H), 5.20 (s, 2H), 2.05 (s, 3H), 2.02 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₆N₃O₄ (M+H)⁺ 456.1923, found 456.1920.

Step 4. Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N,N-dimethylbenzamide (A4a)

To a solution of compound IA5b (40 mg, 0.088 mmol), HBTU (40 mg, 0.11 mmol) and Et₃N (25 μL, 0.18 mmol) in DMF/CH₂Cl₂ (1:1, 10 mL) was added dimethylamine (0.24 μL, 0.26 mmol) and the mixture was allowed to stir at rt for 12 h. After the solvents were removed, the residue was diluted with EtOAc (30 mL) and H₂O (10 mL). After separation, the organic layer was washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to give compound A4a as a white solid (40 mg, 94%). ¹H NMR (CDCl₃, 600 MHz) δ 7.92 (d, J 7.8 Hz, 2H), 7.67 (s, 1H), 7.51 (d, J 7.8 Hz, 2H), 7.34-7.25 (m, 4H), 7.15-7.11 (m, 2H), 7.00-6.95 (m, 3H), 5.21 (s, 2H), 5.13 (s, 2H), 3.06 (s, 3H), 2.92 (s, 3H), 2.16 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃(M+H)⁺ 483.2396, found 483.2410.

Example 9 Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-ethylbenzamide (A4b)

Compounds A4b was prepared from compound IA5b via a HBTU-mediated amide formation in a fashion similar to the one described for compound A4a. White solid, 28% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.93 (d, J=8.4 Hz, 2H), 7.68 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 7.36 (dd, J=7.5, 7.5 Hz, 1H), 7.32-7.28 (m, 2H), 7.27 (s, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.00-6.95 (m, 3H), 6.55-6.50 (m, 1H), 5.24 (s, 2H), 5.15 (s, 2H), 3.50-3.43 (m, 2H), 2.18 (s, 3H), 2.05 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃(M+H)⁺ 483.2396, found 483.2395.

Example 10 Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-isopropylbenzamide (A4c)

Compounds A4c was prepared from compound IA5b via a HBTU-mediated amide formation in a fashion similar to the one described for compound A4a. White solid, 93% yield. H NMR (CDCl₃, 600 MHz) δ 7.91 (d, J=7.8 Hz, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.40-7.36 (m, 2H), 7.30 (dd, J=8.1, 8.1 Hz, 2H), 7.24-7.22 (m, 2H), 7.00-6.96 (m, 3H), 6.09-6.05 (m, 1H), 5.28 (s, 2H), 5.16 (s, 2H), 4.32-4.24 (m, 1H), 2.21 (s, 3H), 2.10 (s, 3H), 1.25 (d, J=6.6 Hz, 6H). HRMS (ESI⁺) calcd for C₃₀H₃₃N₄O₃ (M+H)⁺497.2553, found 497.2558.

Example 11 Synthesis of 3-((3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-phenylbenzamide (A4d)

Compounds A4c was prepared from compound IA5b via a HBTU-mediated amide formation in a fashion similar to the one described for compound A4a. White solid, 49% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.09 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.81 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8, Hz, 2H), 7.44 (dd, J=7.8, 7.8 Hz, 1H), 7.38 (s, 1H), 7.37-7.28 (m, 6H), 7.14 (dd, J=7.2, 7.2 Hz, 1H), 7.00-6.95 (m, 3H), 5.31 (s, 2H), 5.16 (s, 2H), 2.21 (s, 3H), 2.11 (s, 3H). HRMS (ESI⁺) calcd for C₃₃H₃₁N₄O₃ (M+H)⁺531.2396, found 531.2392.

Example 12 Synthesis of N-(3,5-Dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5a) Step 1. Synthesis of (E)-N-(3,5-dimethyl-1H-pyrazol-4-yl)-1-phenylmethanimine (IA6)

To a solution of methyl 3,5-dimethyl-4-nitropyrazole (IA1, 2.82 g, 20 mmol) in MeOH (30 mL) was added Pd/C (280 mg, 10% yield and the mixture was allowed to shake under H₂ (50 psi) with a hydrogenator at rt for 12 h. The catalyst was removed by filtration over a layer of celite. To the resulting filtrate was added benzaldehyde (2.33 g, 22 mmol) and the mixture was heated at reflux for 4 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-80% EtOAc/hexanes) to afford compound IA6 as yellow oil (3.5 g, 88% over two steps). ¹H NMR (CDCl₃, 600 MHz) δ 8.53 (s, 1H), 7.86 (d, J=7.2 Hz, 2H), 7.49-7.40 (m, 3H), 2.42 (s, 3H), 2.41 (s, 3H). HRMS (ESI⁺) calcd for C₁₂H₁₄N₃ (M+H)⁺ 200.1182, found 200.1182.

Step 2. Synthesis of (E)-N-(3,5-Dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)-1-phenylmethanimine (IA8a)

To a solution of compound IA6 (400 mg, 2.0 mmol) in DMF (20 mL) were added KOtBu (518 mg, 2.40 mmol) and the mixture was allowed to stir at rt for 10 min. 4-Nitrobenzyl bromide (IA7a, 269 mg, 2.40 mmol) was then added and the reaction was allowed to stir at rt for additional 12 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-80% EtOAc/hexanes) to afford compound IA8a as a gray solid (430 mg, 64%). ¹H NMR (CDCl₃, 600 MHz) δ 8.54 (s, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.88-7.84 (m, 2H), 7.48-7.42 (m, 3H), 7.24 (d, J=7.8 Hz, 2H), 5.34 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H). HRMS (ESI⁺) calcd for C₁₉H₁₉N₄O₂ (M+H)⁺ 335.1503, found 335.1501.

Step 3. Synthesis of 3,5-Dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-amine (IA9a)

To a solution of imine IA8a (400 mg, 2.0 mmol) in MeOH (20 mL) were added 1 N HCl (5 mL) and the mixture was allowed to stir at rt for 4 h. After the MeOH was evaporated in vacuo, the aqueous phase was extracted with EtOAc to remove the byproduct benzaldehyde. The aqueous layer was basified with saturated NaHCO₃ and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K₂CO₃, and concentrated in vacuo to afford compound IA9a as a yellow oil (220 mg, 74%). ¹H NMR (CDCl₃, 600 MHz) δ 8.15 (d, J=7.8 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 5.25 (s, 2H), 2.21 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₁₂H₁₅N₄O₂ (M+H)⁺ 247.1190, found 247.1190.

Step 4. Synthesis of N-(3,5-Dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5a)

Compounds A5a was prepared from intermediate IA9a, via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. Light yellow solid, 180 mg, 50% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.15 (d, J=7.8 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.60-7.55 (m, 3H), 7.45 (dd, J=7.8 Hz, 1H), 7.33-7.27 (m, 3H), 7.01-6.95 (m, 3H), 6.64 (d, J=7.8 Hz, 1H), 5.66 (s, 2H), 5.17 (s, 2H), 2.23 (s, 3H), 2.13 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₅N₄O₄ (M+H)⁺ 457.1876, found 457.1879.

Example 13 Synthesis of N-(3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5b) Step 1. Synthesis of (E)-N-(3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-1-phenylmethanimine (IA8b)

Intermediate IA8b was prepared with bromide IA7b, in a fashion similar to the one described for intermediate IA8a. Gray solid, 420 mg, 63% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.54 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.89-7.83 (m, 2H), 7.51 (dd, J=7.8, 7.8 Hz, 1H), 7.47-7.40 (m, 4H), 5.33 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H). HRMS (ESI⁺) calcd for C₁₉H₁₉N₄O₂ (M+H)⁺ 335.1503, found 335.1507.

Step 2. Synthesis of 3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-amine (IA9b)

Intermediate IA9b was prepared with bromide IA8b, in a fashion similar to the one described for intermediate IA9a. Yellow oil, 180 mg, 61% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.11 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.47 (dd, J=7.8, 7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 5.25 (s, 2H), 2.21 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₁₂H₁₅N₄O₂ (M+H)⁺247.1190, found 247.1193.

Step 3. Synthesis of N-(3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5b)

Compounds A5b was prepared from intermediate IA9b, via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. Light yellow solid, 180 mg, 54% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.14 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J 7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.51 (dd, J=7.8, 7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.33-7.24 (m, 3H), 7.00-6.97 (m, 3H), 5.32 (s, 2H), 5.16 (s, 2H), 2.21 (s, 3H), 2.15 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₅N₄O₄ (M+H)⁺ 457.1876, found 457.1879.

Example 14 Synthesis of N-(3,5-Dimethyl-1-(2-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5c) Step 1. Synthesis of (E)-N-(3,5-Dimethyl-1-(2-nitrobenzyl)-1H-pyrazol-4-yl)-1-phenylmethanimine (IA8c)

Intermediate IA8c was prepared with bromide IA7c, in a fashion similar to the one described for intermediate IA8a. Gray solid, 450 mg, 67% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.58 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 7.91-7.85 (m, 2H), 7.53 (dd, J=7.2, 7.2 Hz, 1H), 7.50-7.41 (m, 4H), 6.56 (d, J=7.8 Hz, 1H), 5.68 (s, 2H), 2.44 (s, 3H), 2.29 (s, 3H). HRMS (ESI⁺) calcd for C₁₉H₁₉N₄O₂ (M+H)⁺ 335.1503, found 335.1505.

Step 2. Synthesis of 3,5-Dimethyl-1-(2-nitrobenzyl)-1H-pyrazol-4-amine (IA9c)

Intermediate IA9c was prepared with bromide IA8c, in a fashion similar to the one described for intermediate IA9a. Yellow oil, 200 mg, 65% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.13 (d, J=7.8 Hz, 1H), 7.50 (dd, J=7.8, 7.8 Hz, 1H), 7.41 (dd, J=7.8, 7.8 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 5.58 (s, 2H), 2.22 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₁₂H₁₅N₄O₂ (M+H)⁺ 247.1190, found 247.1191.

Step 3. Synthesis of N-(3,5-Dimethyl-1-(2-nitrobenzyl)-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A5c)

Compounds A5c was prepared from intermediate IA9c, via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. Light yellow solid, 200 mg, 54% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.18 (d, J=8.4 Hz, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.32-7.27 (m, 3H), 7.26-7.23 (m, 2H), 7.00-6.95 (m, 3H), 5.32 (s, 2H), 5.15 (s, 2H), 2.21 (s, 3H), 2.12 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₅N₄O₄ (M+H)⁺457.1876, found 457.1878.

Example 15. Synthesis of N-(1-(4-Aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A6a)

To a solution of compound A5a (180 mg, 0.39 mmol) and NiCl₂.6H₂O (188 mg, 0.79 mmol) in MeOH (20 mL) was slowly added NaBH₄ (60 mg, 1.6 mmol) and the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K₂CO₃, and concentrated in vacuo to afford compound A6a as a light yellow solid (150 mg, 90%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.49 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.30 (dd, J=8.1, 8.1 Hz, 2H), 7.02 (d, J=7.8 Hz, 2H), 6.95 (dd, J=7.2, 7.2, Hz, 1H), 6.87 (d, J=7.8 Hz, 2H), 6.50 (d, J=8.4 Hz, 2H), 5.19 (s, 2H), 5.02 (s, 2H), 5.00 (s, 2H), 2.05 (s, 3H), 2.01 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₇N₄O₂ (M+H)⁺ 427.2134, found 427.2134.

Example 16 Synthesis of N-(1-(3-Aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A6b)

Compounds A6b was prepared from A5b, in a fashion similar to the one described for compound A6a. White solid, 100 mg, 60% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.90 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.32-7.24 (m, 3H), 7.08 (dd, J=7.8, 7.8 Hz, 1H), 7.00-6.94 (m, 3H), 6.56 (d, J=7.8 Hz, 1H), 6.52 (d, J=7.8 Hz, 1H), 6.41 (s, 1H), 5.15 (s, 2H), 5.12 (s, 2H), 3.67 (br s, 2H), 2.20 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₇N₄O₂ (M+H)⁺ 427.2134, found 427.2137.

Example 17 Synthesis of N-(1-(2-Aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A6c)

Compounds A6b was prepared from A5b, in a fashion similar to the one described for compound A6a. White solid, 120 mg, 72% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.87 (d, J=7.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.30 (dd, J=8.4, 8.4 Hz, 2H), 7.14-7.07 (m, 3H), 7.00-6.94 (m, 3H), 6.68 (dd, J=7.2, 7.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 5.15 (s, 2H), 5.12 (s, 2H), 4.65 (br s, 2H), 2.18 (s, 3H), 2.17 (s, 3H). HRMS (ESI⁺) calcd for C₂₆H₂₇N₄O₂ (M+H)⁺ 427.2134, found 427.2134.

Example 18 Synthesis of N-(1-(4-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A7a)

To a solution of amine A6a (50 mg, 0.12 mmol) and Et₃N (33 μL, 0.23 mmol) in anhydrous CH₂Cl₂ (10 mL) was added acetic anhydride (17 μL, 0.18 mmol) and the mixture was allowed to stir at rt for 12 h. After the solvents were removed, the residue was diluted with EtOAc (30 mL), H₂O (10 mL) and saturated NaHCO₃ (10 mL). After separation, the organic layer was washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to give compound A7a as a white solid (30 mg, 55%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.93 (s, 1H), 9.52 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.30 (dd, J=7.5, 7.5 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.02 (d, J=7.2 Hz, 2H), 6.95 (dd, J=7.5, 7.5, Hz, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 2.06 (s, 3H), 2.02 (s, 6H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃ (M+H)⁺469.2240, found 469.2241.

Example 19 Synthesis of N-(1-(3-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A7b)

Compounds A7b was prepared from A6b, in a fashion similar to the one described for compound A7a. White solid, 35 mg, 64% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.67 (s, 1H), 7.91 (d, J=7.8 Hz, 2H), 7.76 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.50 (d, J=7.2 Hz, 2H), 7.32-7.27 (m, 2H), 7.25 (dd, J=8.1, 8.1 Hz, 1H), 7.02-6.94 (m, 4H), 6.89 (d, J=7.8 Hz, 1H), 5.17 (s, 2H), 5.12 (s, 2H), 2.10 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃(M+H)⁺ 469.2240, found 469.2245.

Example 20 Synthesis of N-(1-(2-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-(phenoxymethyl)benzamide (A7c)

Compounds A7c was prepared from A6c, in a fashion similar to the one described for compound A7a. White solid, 30 mg, 55% yield. ¹H NMR (CDCl₃, 600 MHz) δ 10.48 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.88 (d, J=7.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.33-7.23 (m, 5H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.00-6.94 (m, 3H), 5.14 (s, 2H), 5.12 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃(M+H)⁺ 469.2240, found 469.2242.

Example 21 Synthesis of N-(3,5-Dimethyl-1-(3-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-N-methyl-4-(phenoxymethyl)benzamide (B1)

To a solution of compound IA4b (50 mg, 0.11 mmol) in THF (2 mL) at 0° C. was added LDA (1 M in THF, 0.2 mL) dropwise. After MeI (76 mg, 0.54 mmol) was added, the resulting mixture was allowed to stir at 0° C. for 3 h. The reaction was quenched with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was dissolved in a solution of MeNH₂ (33 wt. % in absolute ethanol), and the solution was heated at 80° C. overnight. After cooled to rt, the reaction mixture was concentrated and the residue was purified by flash column chromatography (60-80% EtOAc/hexanes) to afford B1 as a white solid (3.7 mg, 7% over two steps). ¹H NMR (CDCl₃, 600 MHz) δ 7.56 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.32-7.23 (m, 7H), 6.98 (t, J=7.4 Hz, 1H), 6.94 (d, J=7.5 Hz, 2H), 6.66 (d, J=7.6 Hz, 1H), 6.05 (br s, 1H), 5.15 (d, J=16.0 Hz, 1H), 5.07 (d, J=16.0 Hz, 1H), 5.00 (s, 2H), 3.32 (s, 3H), 2.98 (d, J=4.7 Hz, 3H), 2.17 (s, 3H), 1.82 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃ (M+H)⁺ 483.2391, found 483.2382.

Example 22 Synthesis of 3-((3,5-Dimethyl-4-((4-(phenoxymethyl)benzyl)amino)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (B2) Step 1. Synthesis of 3-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (IA10

To a solution of 3,5-dimethyl-4-nitropyrazole (IA1, 2.0 g, 14.2 mmol) in DMF (100 mL) were added methyl 3-(bromomethyl)benzoate (IA2c, 3.90 g, 17.0 mmol) and Cs₂CO₃ (9.23 g, 28.3 mmol) and the mixture was allowed to stir at rt for 12 h. The reaction was quenched with water (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was then dissolved in MeNH₂/EtOH (33 wt. %, 25 mL) in a sealed tube and heated at 70° C. for 24 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-20% MeOH/CH₂Cl₂) to afford compound IA10 as a light yellow solid (1.45 g, 36% over two steps). ¹H NMR (CDCl₃, 600 MHz) δ 7.68-7.62 (m, 2H), 7.42 (dd, J=7.2, 7.2 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.14 (br s, 1H), 5.29 (s, 2H), 3.01 (d, J=4.2 Hz, 3H), 2.57 (s, 3H), 2.54 (s, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₇N₄O₃ (M+H)⁺289.1295, found 289.1291.

Step 2. Synthesis of 3-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (IA11)

Compound IA11 was prepared from intermediate IA10 via a NaBH₄/NiCl₂-mediated reduction in a fashion similar to the one described for compound IA3a. Yellow oil, 900 mg, 72% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.63 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.32 (br s, 1H), 5.17 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.19 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₉N₄O (M+H)⁺ 259.1553, found 259.1549.

Step 3. Synthesis of 3-((3,5-Dimethyl-4-((4-(phenoxymethyl)benzyl)amino)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (B2)

A solution of intermediate IA11 (40 mg, 0.16 mmol) and 4-(phenoxymethyl)benzaldehyde (33 mg, 0.16 mmol) in CH₂Cl₂ (3 mL) was allowed to stir at rt overnight. After the solvent was removed, the residue was redissolved in MeOH (3 mL) and the solution was cooled at 0° C. After NaBH₄ (11 mg, 0.29 mmol) was added, the reaction mixture was allowed to stir at 0° C. for 2 h before quenched with Saturated NH₄Cl. The mixture was then extracted with EtOAc and the organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography using (60-80% EtOAc/hexanes) to afford B2 as a yellow solid (15 mg, 21%). ¹H NMR (CDCl₃, 600 MHz) δ 7.61 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 7.36-7.33 (m, 3H), 7.29-7.24 (m, 4H), 7.07 (d, J=7.6 Hz, 1H), 6.97-6.93 (m, 3H), 6.10 (br s, 1H), 5.16 (s, 2H), 5.04 (s, 2H), 3.98 (s, 2H), 2.98 (d, J=4.7 Hz, 3H), 2.15 (s, 3H), 1.84 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₃₁N₄O₂ (M+H)⁺ 455.2442, found 455.2434.

Example 23 Synthesis of 3-((3,5-Dimethyl-4-((4-(phenoxymethyl)phenyl)sulfonamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (B3)

To a solution of intermediate IA11 (37 mg, 0.14 mmol) in THF (3 mL) was added Et₃N (82 μL, 0.57 mmol) and 4-(phenoxymethyl)benzenesulfonyl chloride (61 mg, 0.22 mmol). After the reaction mixture was allowed to stir at rt overnight and then quenched with saturated NH₄Cl, the mixture was extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography using (0-10% MeOH/CH₂Cl₂) to afford B3 as a yellow solid (25 mg, 34%). ¹H NMR (CDCl₃, 600 MHz) δ 7.70 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (t, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.29-7.26 (m, 2H), 7.17 (d, J=7.6 Hz, 1H), 6.97 (t, J=7.1 Hz, 1H), 6.92 (d, J=8.2 Hz, 2H), 6.31-6.26 (m, 1H), 6.24 (s, 1H), 5.18 (s, 2H), 5.12 (s, 2H), 2.95 (d, J=4.8 Hz, 3H), 1.86 (s, 3H), 1.66 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₉N₄O₄S (M+H)⁺ 505.1904, found 505.1902.

Example 24 Synthesis of 3-((3,5-Dimethyl-4-(4-((phenylthio)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C1) Step 1. Synthesis of 3-((4-(4-(Chloromethyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (IA12)

To a solution of amine IA11 (900 mg, 3.49 mmol) and Et₃N (1.00 mL, 7.00 mmol) in anhydrous CH₂Cl₂ (100 mL) was added 4-(chloromethyl)benzoyl chloride (790 mg, 4.19 mmol) and the mixture was allowed to stir at rt for 12 h. After the solvents were removed, the residue was diluted with EtOAc (50 mL) and H₂O (50 mL). After separation, the organic layer was washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to give compound IA12 as a white solid (1.10 g, 61%). ¹H NMR (CDCl₃, 600 MHz) δ 7.92 (d, J=7.8 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.51 (d, J=7.8 Hz, 2H), 7.37 (dd, J=7.2, 7.2 Hz, 1H), 7.29-7.25 (m, 1H), 7.19 (s, 1H), 6.75 (br s, 1H), 5.25 (s, 2H), 4.64 (s, 2H), 2.96 (d, J=4.2 Hz, 3H), 2.17 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₂₂H₂₄ClN₄O₂(M+H)⁺ 411.1582, found 411.1580.

Step 2. Synthesis of 3-((3,5-Dimethyl-4-(4-((phenylthio)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C1)

To a solution of compound IA12 (30 mg, 0.073 mmol) in DMF (5 mL) was added Cs₂CO₃ (36 mg, 0.11 mmol) and thiophenol (8.9 mg, 0.080 mmol) and the reaction mixture was allowed to stir at 50° C. for 14 h. After cooled to rt, the solution was diluted with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford C1 as a white solid (10 mg, 28%). ¹H NMR (CDCl₃, 600 MHz) δ 7.82 (d, J=7.8 Hz, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.45-7.41 (m, 1H), 7.40-7.33 (m, 4H), 7.32-7.29 (m, 1H), 7.29-7.24 (m, 3H), 7.22-7.14 (m, 2H), 6.67-6.60 (m, 1H), 5.26 (s, 2H), 4.15 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.17 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₂S (M+H)⁺ 485.2011, found 485.2011.

Example 25 Synthesis of 3-((3,5-Dimethyl-4-(4-((phenylamino)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C2)

To a solution of compound IA12 (41 mg, 0.10 mmol) in DMF (1 mL) was added DIPEA (70 μL, 0.40 mmol) and aniline (37 mg, 0.40 mmol). The reaction mixture was allowed to stir at 80° C. for 7 h. After cooled to rt, the solution was diluted with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (60-80% EtOAc/hexanes) to afford C2 as a white solid (32 mg, 68%). ¹H NMR (CDCl₃, 600 MHz) δ 7.88 (d, J=8.2 Hz, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.36 (t, J=7.7 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.18-7.14 (m, 3H), 6.75 (br s, 1H), 6.72 (t, J=7.4 Hz, 1H), 6.61 (d, J=7.9 Hz, 2H), 5.23 (s, 2H), 4.42 (s, 2H), 4.23 (br s, 1H), 2.95 (d, J=4.8 Hz, 3H), 2.16 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₃₀N₅O₂ (M+H)⁺ 468.2394, found 468.2402.

Example 26 Synthesis of 3-((3,5-Dimethyl-4-(4-phenethylbenzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C3)

Compounds C3 was prepared from intermediate IA11 via an EDC- or HBTU-mediated amide formation in a fashion similar to the one described for compound A1 or A4a. White solid, 19 mg, 27% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.82 (d, J=7.9 Hz, 2H), 7.74 (d, J=7.9 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 7.30-7.26 (m, 5H), 7.21 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 2H), 7.13 (s, 1H), 6.63 (q, J=4.2 Hz, 1H), 5.28 (s, 2H), 3.03-2.93 (m, 7H), 2.20 (s, 3H), 2.07 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₂ (M+H)⁺467.2442, found 467.2444.

Example 27 Synthesis of N¹-(3,5-Dimethyl-1-(3-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-N⁴-phenylterephthalamide (C4)

Compounds C3 was prepared from intermediate IA11 via an EDC- or HBTU-mediated amide formation in a fashion similar to the one described for compound A1 or A4a. White solid, 19 mg, 27% yield. ¹H NMR (DMSO-d6, 600 MHz) δ 10.34 (s, 1H), 9.71 (s, 1H), 8.42 (q, J=4.1 Hz, 1H), 8.07 (dd, J₁=11.9 Hz, J₂=8.7 Hz, 4H), 7.78 (d, J=7.6 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.67 (s, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.35 (t, J=7.9 Hz, 2H), 7.25 (d, J=7.6 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 5.27 (s, 2H), 2.76 (d, J=4.6 Hz, 3H), 2.08 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₅O₃ (M+H)⁺ 482.2187, found 482.2179.

Example 28 Synthesis of 3-((4-(4-(Benzyloxy)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C5)

Compounds C3 was prepared from intermediate IA11 via an EDC- or HBTU-mediated amide formation in a fashion similar to the one described for compound A1 or A4a. White solid, 26 mg, 57% yield. ¹H NMR (CDCl₃, 600 MHz,) δ 7.89 (d, J=8.7 Hz, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.43 (d, J=7.4 Hz, 2H), 7.40 (t, J=7.4 Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.03 (d, J=8.7 Hz, 2H), 6.88-6.84 (m, 1H), 5.22 (s, 2H), 5.13 (s, 2H), 2.94 (d, J=4.7 Hz, 3H), 2.15 (s, 3H), 2.02 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃ (M+H)⁺ 469.2234, found 469.2244.

Example 29 Synthesis of N-(3,5-Dimethyl-1-(3-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-3-(phenoxymethyl)benzamide (C6)

Compounds C3 was prepared from intermediate IA11 via an EDC- or HBTU-mediated amide formation in a fashion similar to the one described for compound A1 or A4a. White solid, 27 mg, 51% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.01 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (t, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.7 Hz, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.18 (s, 1H), 7.00-6.96 (m, 3H), 6.76-6.71 (m, 1H), 5.23 (s, 2H), 5.12 (s, 2H), 2.95 (d, J=4.7 Hz, 3H), 2.17 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₉N₄O₃ (M+H)⁺ 469.2234, found 469.2241.

Example 30 Synthesis of 3-((4-(4-((Cyclohexyloxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (C7)

Compounds C3 was prepared from intermediate IA11 via an EDC- or HBTU-mediated amide formation in a fashion similar to the one described for compound A1 or A4a. White solid, 9.3 mg, 17% yield. ¹H NMR (DMSO-d₆, 600 MHz) δ 9.52 (s, 1H), 8.46-8.40 (m, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.45-7.40 (m, 3H), 7.26 (d, J=7.8 Hz, 1H), 5.27 (s, 2H), 4.56 (s, 2H), 3.38-3.33 (m, 1H), 2.77 (d, J=4.8 Hz, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.91-1.84 (m, 2H), 1.70-1.64 (m, 2H), 1.33-1.20 (m, 6H). HRMS (ESI⁺) calcd for C₂₈H₃₅N₄O₃ (M+H)⁺ 475.2709, found 475.2707.

Example 31 Synthesis of 3-((3,5-Dimethyl-4-(4-((naphthalen-2-yloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D1)

To a solution of compound IA12 (30 mg, 0.073 mmol) in DMF (5 mL) was added Cs₂CO₃ (36 mg, 0.11 mmol) and 2-naphthol (12 mg, 0.080 mmol) and the reaction mixture was allowed to stir at 50° C. for 14 h. After cooled to rt, the solution was diluted with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford D1 as a white solid (5.0 mg, 13%). ¹H NMR (CDCl₃, 600 MHz) δ 8.00 (d, J=7.8 Hz, 2H), 7.77 (dd, J=6.9, 6.9 Hz, 2H), 7.73 (dd, J=7.5, 7.5 Hz, 2H), 7.66 (d, J=7.8 Hz, 2H), 7.59 (s, 1H), 7.46-7.39 (m, 2H), 7.34-7.29 (m, 3H), 7.24 (d, J=8.4 Hz, 1H), 5.33 (s, 2H), 5.31 (s, 2H), 2.91 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H). HRMS (ESI⁺) calcd for C₃₂H₃₁N₄O₃ (M+H)⁺ 519.2396, found 519.2398.

Example 32 Synthesis of 3-((3,5-Dimethyl-4-(4-((naphthalen-1-yloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D2)

Compound D2 was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. Light yellow solid, 18 mg, 48% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.35 (d, J=8.4 Hz, 1H), 7.96 (d, J=7.2 Hz, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.53-7.48 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.33 (m, 2H), 7.28-7.25 (m, 1H), 7.17 (s, 1H), 6.86 (d, J=7.2 Hz, 1H), 6.65-6.60 (m, 1H), 5.34 (s, 2H), 5.27 (s, 2H), 2.98 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.07 (s, 3H). HRMS (ESI⁺) calcd for C₃₂H₃₁N₄O₃ (M+H)⁺ 519.2396, found 519.2392.

Example 33 Synthesis of 3-((3,5-Dimethyl-4-(4-((o-tolyloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D3a)

Compound D3a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 20 mg, 57% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.91 (d, J=7.8 Hz, 2H), 7.74 (d, J=7.2 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.30-7.27 (m, 2H), 7.15 (s, 1H), 7.09 (d, J=7.8 Hz, 2H), 6.87 (d, J=7.8 Hz, 2H), 6.59-6.53 (m, 1H), 5.29 (s, 2H), 5.13 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.29 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃ (M+H)⁺ 483.2396, found 483.2396.

Example 34 Synthesis of 3-((3,5-Dimethyl-4-(4-((m-tolyloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D3b)

Compound D3b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 25 mg, 71% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.93 (d, J=8.4 Hz, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.26-7.23 (m, 1H), 7.20-7.15 (m, 2H), 6.82-6.78 (m, 2H), 6.78-6.72 (m, 2H), 5.24 (s, 2H), 5.13 (s, 2H), 2.96 (d, J=4.8 Hz, 3H), 2.33 (s, 3H), 2.17 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃(M+H)⁺483.2396, found 483.2393.

Example 35 Synthesis of 3-((3,5-Dimethyl-4-(4-((p-tolyloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D3c)

Compound D3c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 13 mg, 37% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.95 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.26-7.23 (m, 1H), 7.20-7.17 (m, 2H), 7.14 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (dd, J=7.8, 7.8 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.80-6.75 (m, 1H), 5.23 (s, 2H), 5.16 (s, 2H), 2.95 (d, J=4.2 Hz, 3H), 2.31 (s, 3H), 2.16 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃ (M+H)⁺ 483.2396, found 483.2398.

Example 36 Synthesis of 3-((4-(4-((2-Methoxyphenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D4a)

Compound D4a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 22 mg, 60% Yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.91 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.38 (dd, J=7.5, 7.5 Hz, 1H), 7.28-7.26 (m, 1H), 7.16 (s, 1H), 6.98-6.92 (m, 2H), 6.89-6.83 (m, 2H), 6.68-6.62 (m, 1H), 5.26 (s, 2H), 5.24 (s, 2H), 3.91 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.19 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₄ (M+H)⁺ 499.2345, found 499.2348.

Example 37 Synthesis of 3-((4-(4-((3-Methoxyphenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D4b)

Compound D4b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 26 mg, 71% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=8.4 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.24 (d, J=7.2 Hz, 1H), 7.21-7.16 (m, 2H), 6.86-6.81 (m, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.55-6.52 (m, 2H), 5.21 (s, 2H), 5.12 (s, 2H), 3.78 (s, 3H), 2.94 (d, J=4.8 Hz, 3H), 2.14 (s, 3H), 2.02 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₄(M+H)⁺ 499.2345, found 499.2350.

Example 38 Synthesis of 3-((4-(4-((4-Methoxyphenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D4c)

Compound D4c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 28 mg, 77% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.92 (d, J=7.2 Hz, 2H), 7.74 (d, J=7.2 Hz, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.40 (dd, J=7.8, 7.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.15 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 6.84 (d, J=7.8 Hz, 2H), 6.58-6.53 (m, 1H), 5.29 (s, 2H), 5.11 (s, 2H), 3.77 (s, 3H), 3.00 (d, J=4.2 Hz, 3H), 2.21 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₄ (M+H)⁺ 499.2345, found 499.2349.

Example 39 Synthesis of 3-((4-(4-((2-Chlorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D5a)

Compound D5a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 15 mg, 41% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=8.4 Hz, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.42-7.36 (m, 3H), 7.29-7.26 (m, 1H), 7.20 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (s, 1H), 6.97-6.91 (m, 2H), 6.63-6.58 (m, 1H), 5.28 (s, 2H), 5.24 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈ClN₄O₃(M+H)⁺ 503.1850, found 503.1846.

Example 40 Synthesis of 3-((4-(4-((3-Chlorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D5b)

Compound D5b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 36 mg, 95% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=7.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.41 (s, 1H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.28-7.25 (m, 1H), 7.21 (dd, J=8.4, 8.4 Hz, 1H), 7.17 (s, 1H), 7.00-6.95 (m, 2H), 6.88-6.84 (m, 1H), 6.64-6.57 (m, 1H), 5.27 (s, 2H), 5.14 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.07 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈ClN₄O₃(M+H)⁺ 503.1850, found 503.1857.

Example 41 Synthesis of 3-((4-(4-((4-Chlorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D5c)

Compound D5c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 30 mg, 82% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.93 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.34 (s, 1H), 7.10-7.22 (m, 3H), 7.17 (s, 1H), 6.90 (d, J=7.8 Hz, 2H), 6.60-6.54 (m, 1H), 5.29 (s, 2H), 5.13 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈ClN₄O₃(M+H)⁺ 503.1850, found 503.1858.

Example 42 Synthesis of 3-((4-(4-((2-Fluorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D6a)

Compound D6a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 21 mg, 59% yield. ¹H NMR (600 MHz, CDCl₃) δ 7.92 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.35 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.11 (dd, J=12.0, 7.8 Hz, 1H), 7.04 (dd, J=7.8, 7.8 Hz, 1H), 6.99 (dd, J=8.4, 8.4 Hz, 1H), 6.94 (dd, J=12.6, 7.8 Hz, 1H), 6.60-6.57 (m, 1H), 5.28 (s, 2H), 5.23 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈ClN₄O₃(M+H)⁺487.2145, found 487.2146.

Example 43 Synthesis of 3-((4-(4-((3-Fluorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D6b)

Compound D6b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 24 mg, 67% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.93 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.39 (dd, J=8.1, 8.1 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.23 (dd, J=7.8, 7.8 Hz, 1H), 7.17 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.72-6.66 (m, 2H), 6.60-6.54 (m, 1H), 5.28 (s, 2H), 5.14 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.21 (s, 3H), 2.08 (s, 3H).

HRMS (ESI⁺) calcd for C₂₈H₂₈FN₄O₃(M+H)⁺ 487.2145, found 487.2141.

Example 44 Synthesis of 3-((4-(4-((4-Fluorophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D6c)

Compound D6c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 12 mg, 34% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.93 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.42-7.35 (m, 2H), 7.29-7.26 (m, 1H), 7.17 (s, 1H), 6.99 (dd, J=8.4, 8.4 Hz, 2H), 6.94-6.88 (m, 2H), 6.63-6.56 (m, 1H), 5.28 (s, 2H), 5.12 (s, 2H), 2.99 (d, J=4.2 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈FN₄O₃(M+H)⁺ 487.2145, found 487.2147.

Example 45 Synthesis of 3-((4-(4-((2-Cyanophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D7a)

Compound D7a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 30 mg, 83% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.95 (d, J=8.4 Hz, 2H), 7.84 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.52 (dd, J=7.8, 7.8 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.83-6.77 (m, 1H), 5.27 (s, 2H), 5.22 (s, 2H), 2.94 (d, J=4.8 Hz, 3H), 2.15 (s, 3H), 2.03 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈N₅O₃(M+H)⁺494.2192, found 494.2188.

Example 46 Synthesis of 3-((4-(4-((3-Cyanophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D7b)

Compound D7b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 28 mg, 78% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.98 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.39 (dd, J=8.1, 8.1 Hz, 1H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.27 (d, J=5.4 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.22-7.18 (m, 3H), 6.85-6.80 (m, 1H), 5.22 (s, 2H), 5.17 (s, 2H), 2.94 (d, J=4.8 Hz, 3H), 2.15 (s, 3H), 2.03 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈N₅O₃(M+H)⁺ 494.2192, found 494.2195.

Example 47 Synthesis of 3-((4-(4-((4-Cyanophenoxy)methyl)benzamido)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D7c)

Compound D7c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 28 mg, 78% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.95 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 7.42-7.34 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.58-6.54 (m, 1H), 5.28 (s, 2H), 5.21 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈N₅O₃(M+H)⁺494.2192, found 494.2186.

Example 48 Synthesis of 3-((3,5-Dimethyl-4-(4-((2-nitrophenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D8a)

Compound D8a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 9.0 mg, 24% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=8.4 Hz, 2H), 7.89 (dd, J=8.1, 1.5 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.53 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (s, 1H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.17 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.62-6.56 (m, 1H), 5.31 (s, 2H), 5.28 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₅O₅ (M+H)⁺ 514.2090, found 514.2092.

Example 49 Synthesis of 3-((3,5-Dimethyl-4-(4-((3-nitrophenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D8b)

Compound D8b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 14 mg, 37% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.97 (d, J=7.2 Hz, 2H), 7.86 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.54-7.50 (m, 1H), 7.46 (dd, J=8.1, 8.1 Hz, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.31 (dd, J=8.4, 1.2 Hz, 1H), 7.28-7.26 (m, 1H), 7.18 (s, 1H), 6.67-6.62 (m, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 2.98 (d, J=4.8 Hz, 3H), 2.18 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₅O₅ (M+H)⁺ 514.2090, found 514.2093.

Example 50 Synthesis of 3-((3,5-Dimethyl-4-(4-((4-nitrophenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D8c)

Compound D8c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 23 mg, 61% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.21 (d, J=9.0 Hz, 2H), 7.99 (d, J=7.8 Hz, 2H), 7.72 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.35 (dd, J=8.1, 8.1 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.79-6.73 (m, 1H), 5.25 (s, 2H), 5.23 (s, 2H), 2.95 (d, J=4.8 Hz, 3H), 2.15 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈N₅O₅ (M+H)⁺ 514.2090, found 514.2088.

Example 51 Synthesis of 3-((3,5-Dimethyl-4-(4-((2-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D9a)

Compound D9a was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 31 mg, 79% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.96 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.48 (dd, J=8.1, 8.1 Hz, 1H), 7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.18 (s, 1H), 7.06-7.00 (m, 2H), 6.89-6.83 (m, 1H), 5.24 (s, 2H), 5.20 (s, 2H), 2.93 (d, J=4.8 Hz, 3H), 2.14 (s, 3H), 2.02 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈F₃N₄O₃(M+H)⁺ 537.2114, found 537.2108.

Example 52 Synthesis of 3-((3,5-Dimethyl-4-(4-((3-(trifluoromethyl)phenoxy)-methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D9b)

Compound D9b was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 17 mg, 43% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.96 (d, J=7.2 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.60-7.53 (m, 3H), 7.41 (dd, J=7.8, 7.8 Hz, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.28-7.21 (m, 3H), 7.18 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.73-6.68 (m, 1H), 5.25 (s, 2H), 5.18 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.18 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈F₃N₄O₃(M+H)⁺537.2114, found 537.2112.

Example 53 Synthesis of 3-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)-methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D9c)

Compound D9c was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 7.0 mg, 18% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=8.4 Hz, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 4H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.32 (s, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.17 (s, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.58-6.53 (m, 1H), 5.29 (s, 2H), 5.20 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.21 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈F₃N₄O₃(M+H)⁺537.2114, found 537.2119.

Example 54 Synthesis of 3-((3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)-methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (D10)

Compound D10 was prepared from intermediate IA12 via a displacement reaction by a phenol in a fashion similar to the one described for compound D1. White solid, 14 mg, 16% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.96 (d, J=7.8 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 7.44-7.40 (m, 2H), 7.37 (d, J=7.5, 7.5 Hz, 1H), 7.29-7.26 (m, 1H), 7.17 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.67 (d, J=3.6 Hz, 1H), 5.26 (s, 2H), 5.21 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₃₀H₃₀F₃N₄O₃(M+H)⁺ 551.2270, found 551.2265.

Example 55 Synthesis of N-(1-(3-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (D11) Step 1. Synthesis of N-(3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (IA17)

Compound IA17 was prepared from intermediate IA9b and 4-((4-(trifluoromethyl)phenoxy)methyl)benzoic acid via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. Yellow solid, 110 mg, 42% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.14 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J=7.2 Hz, 2H), 7.60-7.54 (m, 4H), 7.52 (dd, J=7.8, 7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 5.20 (s, 2H), 2.22 (s, 3H), 2.15 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₄F₃N₄O₄(M+H)⁺ 525.1744, found 525.1743.

Step 2. Synthesis of N-(1-(3-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (D1)

Compound D11 was prepared from intermediate IA17 through a NaBH₄/NiCl₂-mediated reduction followed by an acetylation reaction in a fashion similar to the one described for compound A7a. White solid, 10 mg, 18% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.34 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.65 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.51 (d, J=7.8 Hz, 2H), 7.26-7.23 (m, 2H), 7.06 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.89 (d, J=7.2 Hz, 1H), 5.18 (s, 2H), 5.17 (s, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈F₃N₄O₃ (M+H)⁺ 537.2114, found 537.2110.

Example 56 Synthesis of N-(1-(3-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamide (D12) Step 1. Synthesis of 4,4,5,5-Tetramethyl-2-(2-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (IA14)

A flask charged with Pd(dppf)Cl₂ (44 mg, 0.06 mmol), KOAc (589 mg, 6.0 mmol), and bis(pinacolato)diboron (559 mg, 2.2 mmol) was flushed with nitrogen. DMSO (10 mL) and 4-bromo-3-methylbenzotrifluoride (IA13, 280 mg, 2.0 mmol) were then added. After being stirred at 80° C. for 24 h, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to give compound IA14 as a colorless oil (380 mg, 66%). ¹H NMR (CDCl₃, 600 MHz) δ 7.84 (d, J=7.8 Hz, 1H), 7.42-7.37 (m, 2H), 2.58 (s, 3H), 1.35 (s, 12H).

Step 2. Synthesis of 2-Methyl-4-(trifluoromethyl)phenol (IA15)

To a solution of compound IA14 (380 mg, 1.33 mmol) in EtOH/H₂O (2:1, 6 mL) was added mCPBA (252 mg, 1.46 mmol) and the mixture was allowed to stir at rt for 12 h. After the solvents were removed, the residue was diluted with EtOAc (20 mL), H₂O (10 mL) and saturated NaHCO₃ (10 mL). After separation, the organic layer was washed with brine (20 mL) and concentrated. The residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to give phenol IA15 as a white solid (180 mg, 77%). ¹H NMR (CDCl₃, 600 MHz) δ 7.55 (s, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 2.10 (s, 3H). HRMS (ESI) calcd for C₈H₆F₃O (M−H)⁻ 175.0376, found 175.0378.

Step 3. Synthesis of 4-((2-Methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic Acid (IA16)

To a solution of methyl 4-(bromomethyl)benzoate (IA2b, 220 mg, 0.88 mmol) in DMF (10 mL) was added Cs₂CO₃ (573 mg, 1.76 mmol) and 2-methyl-4-trifluoromethylphenol (IA15, 170 mg, 0.97 mmol) and the reaction mixture was allowed to stir at 80° C. for 12 h. After cooled to rt, the solution was diluted with saturated NH₄Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and 1 N NaOH (10 mL). The reaction mixture was allowed to stir at rt for 12 h. Upon removal of MeOH, aqueous phase was acidified with 1 N HCl to pH=3. Aqueous solution was extracted with EtOAc, The organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford acid IA16 as a white solid (130 mg, 45% over two steps). ¹H NMR (DMSO-d₆, 600 MHz) δ 7.97 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.2 Hz, 2H), 7.55 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 5.31 (s, 2H), 2.29 (s, 3H). HRMS (ESI⁻) calcd for C₁₆H₁₂F₃O₃ (M−H)⁻ 309.0744, found 309.0739.

Step 4. Synthesis of N-(3,5-Dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamide (IA18)

Compound IA18 was prepared from intermediate IA9b and 4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzoic acid (IA16) via an EDC-mediated amide formation in a fashion similar to the one described for compound A1. Yellow solid, 75 mg, 50% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.15 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.52 (dd, J=7.8, 7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.43-7.39 (m, 2H), 7.29 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 5.33 (s, 2H), 5.22 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₆F₃N₄O₄(M+H)⁺ 539.1901, found 539.1906.

Step 5. Synthesis of N-(1-(3-Acetamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamide (D12)

Compound D12 was prepared from intermediate IA18 through a NaBH₄/NiCl₂-mediated reduction followed by an acetylation reaction in a fashion similar to the one described for compound A7a. White solid, 6.0 mg, 14% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.18 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.44-7.37 (m, 2H), 7.26-7.22 (m, 1H), 7.07 (s, 1H), 6.92-6.84 (m, 2H), 5.19 (s, 4H), 2.32 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₃₀H₃₀F₃N₄O₃ (M+H)⁺ 551.2270, found 551.2270.

Example 57 Synthesis of 6-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)-benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E1a) Step 1. Synthesis of Methyl 6-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)picolinate (IE3a)

A solution of IE1a (600 mg, 4.0 mmol), NBS (712 mg, 4.0 mmol) and AIBN (131 mg, 0.8 mmol) in CCl₄ (15 mL) was heated at 70° C. for 2 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford an inseparable mixture of IE2a and IE1a. To a solution of 3,5-dimethyl-4-nitropyrazole (141 mg, 1.0 mmol) and KO^(t)Bu (135 mg, 1.2 mmol) in DMF (5 ml) was added the above mixture and the reaction mixture was allowed to stir rt for 12 h. The reaction was quenched with NH₄Cl (sat.) and EtOAc (50 mL) was added. The organic layer was separated, washed with H₂O (150 mL) and brine (100 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (0-80% EtOAc/hexanes) to afford compound IE3a as a light yellow oil (230 mg, 79%). ¹H NMR (CDCl₃, 600 MHz) δ 8.08 (d, J=7.8 Hz, 1H), 7.84 (dd, J=7.8, 7.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 5.49 (s, 2H), 4.02 (s, 3H), 2.63 (s, 3H), 2.55 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₅N₄O₄ (M+H)⁺ 291.1093, found 291.1098.

Step 2. Synthesis of 6-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (IE4a)

A solution of methyl ester IE3a (200 mg, 0.69 mmol) in MeNH₂/EtOH (5 mL) in a sealed tube was heated at 70° C. for 24 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IE4a as a light yellow solid (130 mg, 65%). ¹H NMR (CDCl₃, 600 MHz) δ 8.16 (d, J=8.4 Hz, 1H), 7.85 (dd, J=8.1, 8.1 Hz, 1H), 7.78 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 5.39 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.63 (s, 3H), 2.55 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₆N₅O₃ (M+H)⁺ 290.1253, found 290.1259.

Step 3. Synthesis of 6-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (IE5a)

To a solution of compound IE4a (130 mg, 0.45 mmol) and NiCl₂.6H₂O (214 mg, 0.90 mmol) in MeOH (20 mL) was slowly added NaBH₄ (68 mg, 1.80 mmol) and the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine and dried over anhydrous K₂CO₃. After filtration, the filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IE5a as a brown solid (90 mg, 77%). ¹H NMR (CDCl₃, 600 MHz) δ 8.07 (d, J=7.2 Hz, 1H), 7.96 (br s, 1H), 7.74 (dd, J=7.2, 7.2 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 5.29 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.31 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₈N₅O (M+H)⁺ 260.1511, found 260.1509.

Step 4. Synthesis of 6-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E1a)

Compound E1a was prepared from amine IE5a and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (7.5 mg, 9%). ¹H NMR (CDCl₃, 600 MHz) δ 8.09 (d, J=7.8 Hz, 1H), 7.98 (d, J=4.2 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.79 (dd, J=7.8, 7.8 Hz, 1H), 7.56 (d, J=7.8 Hz, 4H), 7.29 (s, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 5.37 (s, 2H), 5.20 (s, 2H), 3.06 (d, J=4.8 Hz, 3H), 2.21 (s, 3H), 2.18 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₇F₃N₅O₃(M+H)⁺ 538.2066, found 538.2063.

Example 58 Synthesis of 6-((3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E1b)

Compound E1b was prepared from amine IE5a and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (17 mg, 40%). ¹H NMR (CDCl₃, 600 MHz) δ 8.10 (d, J=7.8 Hz, 1H), 7.98 (br s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.80 (dd, J=8.4, 8.4 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.44-7.39 (m, 2H), 7.26-7.23 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.38 (s, 2H), 5.22 (s, 2H), 3.06 (d, J=5.4 Hz, 3H), 2.34 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₉F₃N₅O₃(M+H)⁺ 552.2222, found 552.2230.

Example 59 Synthesis of 4-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E2a) Step 1. Synthesis of Methyl 4-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)picolinate (IE3b)

Compound IE3b was prepared in a fashion similar to the one described for compound IE3a. White solid (270 mg, 66%). ¹H NMR (CDCl₃, 600 MHz) δ 8.74 (d, J=4.8 Hz, 1H), 7.92 (s, 1H), 7.19 (d, J=3.6 Hz, 1H), 5.34 (s, 2H), 4.02 (s, 3H), 2.58 (s, 3H), 2.55 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₅N₄O₄ (M+H)⁺ 291.1093, found 291.1098.

Step 2. Synthesis of 4-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (IE4b)

Compound IE4b was prepared in a fashion similar to the one described for compound IE4a. Whit solid (180 mg, 90%). ¹H NMR (CDCl₃, 600 MHz) δ 8.52 (d, J=4.2 Hz, 1H), 8.01 (s, 1H), 7.98 (br s, 1H), 7.09 (d, J=3.6 Hz, 1H), 5.33 (s, 2H), 3.04 (d, J=5.4 Hz, 3H), 2.56 (s, 3H), 2.55 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₆N₅O₃ (M+H)⁺ 290.1253, found 290.1248.

Step 3. Synthesis of 4-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (IE5b)

Compound IE5b was prepared in a fashion similar to the one described for compound IE5a. Brown solid (80 mg, 59%). ¹H NMR (CDCl₃, 600 MHz) δ 8.43 (d, J=4.8 Hz, 1H), 7.99 (br s, 1H), 7.93 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 5.22 (s, 2H), 3.02 (d, J=5.4 Hz, 3H), 2.20 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₈N₅O (M+H)⁺ 260.1511, found 260.1505.

Step 4. Synthesis of 4-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E2a)

Compound E2a was prepared from amine IE5b and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (11 mg, 13%). ¹H NMR (CDCl₃, 600 MHz) δ 8.48 (d, J=4.2 Hz, 1H), 8.00 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.56 (d, J=7.8 Hz, 4H), 7.31 (s, 1H), 7.08 (d, J=4.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 5.20 (s, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.21 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₇F₃N₅O₃(M+H)⁺ 538.2066, found 538.2068.

Example 60 Synthesis of 4-((3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E2b)

Compound E2b was prepared from amine IE5b and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (16 mg, 16%). ¹H NMR (CDCl₃, 600 MHz) δ 8.47 (d, J=4.2 Hz, 1H), 8.01 (d, J=4.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.44-7.38 (m, 3H), 7.08 (d, J=4.8 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 5.21 (s, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.34 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₉F₃N₅O₃(M+H)⁺ 552.2222, found 552.2224.

Example 61 Synthesis of 5-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylnicotinamide (E3a) Step 1. Synthesis of Methyl 5-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)nicotinate (IE3c)

Compound IE3c was prepared in a fashion similar to the one described for compound IE3a. Light yellow oil (230 mg, 79%). ¹H NMR (CDCl₃, 600 MHz) δ 9.19 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 5.33 (s, 2H), 3.97 (s, 3H), 2.63 (s, 3H), 2.54 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₅N₄O₄ (M+H)⁺ 291.1093, found 291.1095.

Step 2. Synthesis of 5-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)-N-methylnicotinamide (IE4c)

Compound IE4c was prepared in a fashion similar to the one described for compound IE4a. White solid (150 mg, 75%). ¹H NMR (CDCl₃, 600 MHz) δ 8.89 (d, J=1.8 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 7.97 (s, 1H), 6.21 (br s, 1H), 5.31 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.62 (s, 3H), 2.53 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₆N₅O₃ (M+H)⁺ 290.1253, found 290.1260.

Step 3. Synthesis of 5-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylnicotinamide (IE5c)

Compound IE5c was prepared in a fashion similar to the one described for compound IE5a. White solid (50 mg, 40%). ¹H NMR (CDCl₃, 600 MHz) δ 8.88 (s, 1H), 8.47 (s, 1H), 7.74 (s, 1H), 6.19 (br s, 1H), 5.25 (s, 2H), 3.10 (d, J=4.2 Hz, 3H), 2.20 (s, 3H), 2.06 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₈N₅O (M+H)⁺ 260.1511, found 260.1511.

Step 4. Synthesis of 5-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylnicotinamide (E3a)

Compound E3a was prepared from amine IE5c and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (30 mg, 48%). ¹H NMR (CDCl₃, 600 MHz) δ 8.97 (s, 1H), 8.60 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.59-7.54 (m, 4H), 7.40 (s, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.71 (br s, 1H), 5.32 (s, 2H), 5.22 (s, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.11 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₇F₃N₅O₃(M+H)⁺ 538.2066, found 538.2061.

Example 62 Synthesis of 5-((3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylnicotinamide (E3b)

Compound E3b was prepared from amine IE5c and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (38 mg, 59%). ¹H NMR (CDCl₃, 600 MHz) δ 8.97 (s, 1H), 8.60 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.8 Hz, 2H), 7.44-7.35 (m, 4H), 6.90 (d, J=8.4 Hz, 1H), 6.74 (br s, 1H), 5.31 (s, 2H), 5.22 (s, 2H), 3.02 (d, J=4.2 Hz, 3H), 2.34 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₉F₃N₅O₃ (M+H)⁺ 552.2222, found 552.2221.

Example 63 Synthesis of 2-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylisonicotinamide (E4a) Step 1. Synthesis of Methyl 2-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)isonicotinate (IE3d)

Compound IE3d was prepared in a fashion similar to the one described for compound IE3a. Light yellow solid (400 mg, 64%). ¹H NMR (CDCl₃, 600 MHz) δ 8.72 (d, J=5.4 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.68 (s, 1H), 5.43 (s, 2H), 3.96 (s, 3H), 2.66 (s, 3H), 2.53 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₅N₄O₄ (M+H)⁺ 291.1093, found 291.1099.

Step 2. Synthesis of 2-((3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl)-N-methylisonicotinamide (IE4d)

Compound IE4d was prepared in a fashion similar to the one described for compound IE4a. White solid (300 mg, 75%). ¹H NMR (CDCl₃, 600 MHz) δ 8.68 (d, J=4.8 Hz, 1H), 7.53 (d, J=4.8 Hz, 1H), 7.45 (s, 1H), 6.24 (br s, 1H), 5.41 (s, 2H), 3.02 (d, J=5.4 Hz, 3H), 2.65 (s, 3H), 2.53 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₆N₅O₃ (M+H)⁺ 290.1253, found 290.1254.

Step 3. Synthesis of 2-((4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-methylisonicotinamide (IE5d)

Compound IE5d was prepared in a fashion similar to the one described for compound IE5a. Brown oil (150 mg, 55%). ¹H NMR (CDCl₃, 600 MHz) δ 8.62 (d, J=4.8 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.11 (s, 1H), 6.64 (br s, 1H), 5.30 (s, 2H), 2.95 (d, J=4.8 Hz, 3H), 2.18 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₁₃H₁₈N₅O (M+H)⁺ 260.1511, found 260.1507.

Step 4. Synthesis of 2-((3,5-Dimethyl-4-(4-((4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylisonicotinamide (E4a)

Compound E4a was prepared from amine IE5d and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (10 mg, 16%). ¹H NMR (CDCl₃, 600 MHz) δ 8.67 (d, J=5.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.69 (d, J=4.2 Hz, 1H), 7.60-7.53 (m, 5H), 7.44 (s, 1H), 7.07-7.02 (m, 2H), 6.57 (s, 1H), 5.44 (s, 2H), 5.21 (s, 2H), 3.01 (d, J=4.8 Hz, 3H), 2.22 (s, 3H), 2.17 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₇F₃N₅O₃(M+H)⁺ 538.2066, found 538.2062.

Example 64 Synthesis of 2-((3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylisonicotinamide (E4b)

Compound E4b was prepared from amine IE5d and a proper carboxylic acid via an amide formation reaction (EDC coupling). White solid (30 mg, 47%). ¹H NMR (CDCl₃, 600 MHz) δ 8.68 (d, J=4.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.70 (d, J=5.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.44-7.36 (m, 3H), 7.14 (br s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.55 (s, 1H), 5.44 (s, 2H), 5.23 (s, 2H), 3.01 (d, J=4.2 Hz, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₉F₃N₅O₃(M+H)⁺ 552.2222, found 552.2221.

Example 65 Synthesis of N-(3,5-Dimethyl-1-(3-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-6-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)nicotinamide (E5a) Step 1. Synthesis of Methyl 6-(Bromomethyl)nicotinate (IE7)

A solution of IE6 (600 mg, 4.0 mmol), NBS (712 mg, 4.0 mmol) and AIBN (131 mg, 0.8 mmol) in CCl₄ (15 mL) was heated at 70° C. for 2 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford an inseparable mixture of IE6 and IE7, which was directly used for next reaction.

Step 2. Synthesis of Methyl 6-((2-Methyl-4-(trifluoromethyl)phenoxy)methyl)nicotinate (IE8)

To a solution of methyl 6-(bromomethyl)nicotinate (IE7, 200 mg, 0.88 mmol) and 2-methyl-4-(trifluoromethyl)phenol (IA15, 170 mg, 0.97 mmol) in DMF (20 mL) was added Cs₂CO₃ (573 mg, 1.76 mmol) and the mixture was allowed to stir at rt for 12 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford IE8 as a colorless oil (180 mg, 63%). ¹H NMR (CDCl₃, 600 MHz) δ 9.21 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=9.0 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 2.39 (s, 3H). HRMS (ESI⁺) calcd for C₁₆H₁₅F₃NO₃ (M+H)⁺ 326.0999, found 326.1001.

Step 3. Synthesis of 6-((2-Methyl-4-(trifluoromethyl)phenoxy)methyl)nicotinic Acid (IE9)

To a solution of IE8 (180 mg, 0.55 mmol) in MeOH/H₂O (20 mL, 2:1) was added NaOH (45 mg, 1.11 mmol) and the mixture was allowed to stir at rt for 12 h. Upon removal of MeOH, the pH of the reaction mixture was adjusted to 5 and the mixture was extracted with EtOAc. The organic phase was washed with water and brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated in vacuo to afford IE9 as a white solid (100 mg, 58%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.05 (s, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H), 2.33 (s, 3H). HRMS (ESI⁻) calcd for C₁₅H₂₁N₄O (M−H)⁻ 310.0697, found 310.0697.

Step 4. Synthesis of N-(3,5-Dimethyl-1-(3-(methylcarbamoyl)benzyl)-1H-pyrazol-4-yl)-6-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)nicotinamide (E5a)

Compound E5a was prepared from amine IA11 and IE9 via an amide formation reaction (EDC coupling). White solid (17 mg, 31%). ¹H NMR (CDCl₃, 600 MHz) δ 9.13 (d, J=1.8 Hz, 1H), 8.28 (dd, J=8.4, 1.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.48-7.37 (m, 4H), 7.28 (d, J=7.2 Hz, 1H), 7.23 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.52-6.48 (m, 1H), 5.34 (s, 2H), 5.28 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 2.09 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₉F₃N₅O₃ (M+H)⁺ 552.2217, found 552.2224.

Example 66 Synthesis of 4-((3,5-Dimethyl-4-(6-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)nicotinamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E5b)

Compound E5b was prepared from amine IE5b and IE9 via an amide formation reaction (EDC coupling). White solid (10 mg, 18%). ¹H NMR (CDCl₃, 600 MHz) δ 9.14 (s, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.04-7.98 (m, 1H), 7.86 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.10 (d, J=4.2 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.33 (s, 2H), 5.30 (s, 2H), 3.02 (d, J=5.4 Hz, 3H), 2.39 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₈F₃N₆O₃(M+H)⁺ 553.2175, found 553.2178.

Example 67 Synthesis of 3-((3,5-Dimethyl-4-(4-phenoxybenzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (E6a)

Compound E6a was prepared from amine IA11 and 4-phenoxylbenzoic acid via an amide formation reaction (EDC coupling). White solid (20 mg, 46%). ¹H NMR (CDCl₃, 600 MHz) δ 7.91 (d, J=8.8 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (dd, J=7.9, 7.9 Hz, 2H), 7.36 (dd, J=7.6, 7.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.19 (dd, J=7.3, 7.3 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H), 6.78-6.73 (m, 1H), 5.24 (s, 2H), 2.95 (d, J=4.8 Hz, 3H), 2.16 (s, 3H), 2.04 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₇N₄O₃ (M+H)⁺ 455.2078, found 455.2077.

Example 68 Synthesis of 3-((3,5-Dimethyl-4-(4-(4-(trifluoromethyl)phenoxy)-benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (E6b)

Compound E6b was prepared from amine IA11 and 4-(4-(trifluoromethyl)phenoxyl)benzoic acid via an amide formation reaction (EDC coupling). White solid (5 mg, 12%). ¹H NMR (CDCl₃, 600 MHz) δ 8.08 (d, J=9.0 Hz, 2H), 7.76-7.71 (m, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.41-7.36 (m, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J=8.4 Hz, 4H), 6.64-6.59 (m, 1H), 5.28 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.08 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₆F₃N₄O₃(M+H)⁺ 523.1957, found 523.1954.

Example 69 Synthesis of 3-((3,5-Dimethyl-4-(4-(2-methyl-4-(trifluoromethyl)phenoxy)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (E6c) Step 1. Synthesis of Methyl 4-(2-Methyl-4-(trifluoromethyl)phenoxy)benzoate (IE12)

A mixture of phenol IE10 (608 mg, 4.0 mmol), bromide IE11 (956 mg, 4.0 mmol), CuI (152 mg, 0.80 mmol), picolinic acid (197 mg, 1.60 mmol), and K₃PO₄ (2.55 g, 12.0 mmol) in DMSO (10 mL) in a sealed tube was evacuated and backfilled with argon. The reaction mixture was heated at 90° C. for 24 h and then diluted with EtOAc (10 mL) and water (1 mL), and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated, and the residue was purified by flash column chromatography (0-30% EtOAc/hexanes) to afford IE12 as a colorless oil (100 mg, 8%). ¹H NMR (CDCl₃, 600 MHz) δ 8.02 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 3.91 (s, 3H), 2.28 (s, 3H).

Step 2. Synthesis of 4-(2-Methyl-4-(trifluoromethyl)phenoxy)benzoic Acid (IE13)

To a solution of IE12 (100 mg, 0.32 mmol) in MeOH/H₂O (20 mL, 2:1) was added NaOH (26 mg, 0.64 mmol) and the mixture was allowed to stir at rt for 12 h. Upon removal of MeOH, the pH of the reaction mixture was adjusted to 5 and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated in vacuo to afford IE13 as a white solid (80 mg, 84%). ¹H NMR (DMSO-d₆, 600 MHz) δ 7.96 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 2.28 (s, 3H). HRMS (ESI⁻) calcd for C₁₅H₂₁N₄O (M−H)⁻ 295.0588, found 295.0587.

Step 3. Synthesis of 3-((3,5-Dimethyl-4-(4-(2-methyl-4-(trifluoromethyl)phenoxy)-benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (E6c)

Compound E6b was prepared from amine IA11 and IE13 via an amide formation reaction (EDC coupling). White solid (36 mg, 67%). ¹H NMR (CDCl₃, 600 MHz) δ 7.94 (d, J=9.0 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.35 (dd, J=7.2, 7.2 Hz, 1H), 7.17 (s, 1H), 7.11 (dd, J=8.4, 8.4 Hz, 1H), 7.00 (dd, J=8.4, 2.4 Hz, 2H), 6.83 (br s, 1H), 5.22 (s, 2H), 2.94 (d, J=4.8 Hz, 3H), 2.30 (s, 3H), 2.15 (s, 3H), 2.03 (s, 3H). HRMS (ESI⁺) calcd for C₂₉H₂₈F₃N₄O₃(M+H)⁺ 537.2114, found 537.2118.

Example 70 Synthesis of 4-((3,5-Dimethyl-4-(4-(4-(trifluoromethyl)phenoxy)-benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E7a)

Compound E7a was prepared from amine IE5b and 4-(4-(trifluoromethyl)phenoxyl)benzoic acid via an amide formation reaction (EDC coupling). White solid (20 mg, 38%). ¹H NMR (CDCl₃, 600 MHz) δ 8.47 (d, J=4.2 Hz, 1H), 8.04-7.98 (m, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.90 (s, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.34 (s, 1H), 7.13 (d, J=9.0 Hz, 4H), 7.09 (d, J=4.8 Hz, 1H), 5.30 (s, 2H), 3.02 (d, J=5.4 Hz, 3H), 2.21 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₅F₃N₅O₃(M+H)⁺ 524.1909, found 524.1913.

Example 71 Synthesis of 4-((3,5-Dimethyl-4-(4-(2-methyl-4-(trifluoromethyl)phenoxy)-benzamido)-1H-pyrazol-1-yl)methyl)-N-methylpicolinamide (E7b)

Compound E7b was prepared from amine IE5b and IE13 via an amide formation reaction (EDC coupling). White solid (14 mg, 26%). ¹H NMR (CDCl₃, 600 MHz) δ 8.47 (d, J=4.8 Hz, 1H), 8.04-7.98 (m, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.87 (s, 1H), 7.56 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.34 (s, 1H), 7.09 (d, J=4.2 Hz, 1H), 7.03-6.99 (m, 3H), 5.30 (s, 2H), 3.01 (d, J=4.8 Hz, 3H), 2.31 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H). HRMS (ESI⁺) calcd for C₂₈H₂₇F₃N₅O₃(M+H)⁺ 538.2066, found 538.2069.

Example 72 Synthesis of 3-((3,5-Dimethyl-4-(4-(1-phenoxyethyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (F1)

To a solution of 4-(1-phenoxyethyl)benzoic acid (40 mg, 0.165 mmol), HBTU (53.7 mg, 0.142 mmol) and DIPEA (61 mg, 0.472 mmol) in DMF (5 mL) was added IA11 (35 mg, 0.136 mmol), and the mixture was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc (50 mL), washed successively with 1N HCl (15 mL), sat. NaHCO₃ (15 mL) and brine (15 mL), dried over Na₂SO₄. After filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography (5% MeOH/CH₂Cl₂) to provide product F1 as a white solid (26.6 mg, 41%). ¹H NMR (CDCl₃, 600 MHz) δ 7.88 (d, J=8.3 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.2, 2H), 7.44 (s, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.26-7.24 (m, 1H), 7.22-7.18 (m, 2H), 7.15 (s, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.85 (d, J=7.6 Hz, 2H), 6.69-6.64 (m, 1H), 5.38 (q, J=6.4 Hz, 1H), 5.25 (s, 2H), 2.97 (d, J=4.7 Hz, 3H), 2.16 (s, 3H), 2.04 (s, 3H), 1.66 (d, J=7.0 Hz, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃ (M+H)⁺ 483.2396, found 483.2380.

Example 73 Synthesis of 3-(1-(3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)ethyl)-N-methylbenzamide (F2) Step 1. Synthesis of Methyl 3-(1-Hydroxyethyl)benzoate (IF3a)

To a solution of compound IF2a (440 mg, 2.5 mmol) in MeOH (25 mL) was slowly added NaBH₄ (211 mg, 5.6 mmol) and the mixture was allowed to stir at rt for 2 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-80% EtOAc/hexanes) to afford compound IF3a as a white solid (400 mg, 90%). ¹H NMR (CDCl₃, 600 MHz) δ 8.03 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.41 (dd, J=7.8, 7.8 Hz, 1H), 4.95-4.91 (m, 1H), 3.91 (s, 3H), 1.50 (d, J=7.8 Hz, 3H).

Step 2. Synthesis of Methyl 3-(1-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)ethyl)benzoate (IF4a)

To a solution of compound IF3a (100 mg, 0.56 mmol), 3,5-dimethyl-4-nitropyrazole (86 mg, 0.61 mmol) and PPh₃ (176 mg, 0.67 mmol) in THF (40 mL) was slowly added DEAD (116 mg, 0.67 mmol) and the mixture was allowed to stir at rt for 12 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford IF4a as a colorless oil (50 mg, 29%). ¹H NMR (CDCl₃, 600 MHz) δ 7.97 (d, J=7.2 Hz, 1H), 7.91 (s, 1H), 7.42 (dd, J=7.2, 7.2 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 5.46 (q, J=7.2 Hz, 1H), 3.92 (s, 3H), 2.56 (s, 3H), 2.55 (s, 3H), 1.93 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₅H₁₈N₃O₄ (M+H)⁺ 304.1292, found 304.1294.

Step 3. Synthesis of 3-(1-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)ethyl)-N-methylbenzamide (IF5a)

A solution of methyl ester IF4a (50 mg, 0.17 mmol) in MeNH₂/EtOH (5 mL) in a sealed tube was heated at 70° C. for 24 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IF5a as a white solid (40 mg, 80%). ¹H NMR (CDCl₃, 600 MHz) δ 7.71 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.38 (dd, J=7.8, 7.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.28 (br s, 1H), 5.46 (q, J=7.2 Hz, 1H), 3.00 (d, J=4.8 Hz, 3H), 2.54 (s, 3H), 2.54 (s, 3H), 1.92 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₅H₁₉N₄O₃ (M+H)⁺ 303.1452, found 303.1460.

Step 4. Synthesis of 3-(1-(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-methylbenzamide (IF6a)

To a solution of compound IF5a (40 mg, 0.13 mmol) and NiCl₂.6H₂O (62 mg, 0.26 mmol) in MeOH (10 mL) was slowly added NaBH₄ (20 mg, 0.52 mmol) and the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K₂CO₃, and concentrated in vacuo. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IF6a as a brown solid (30 mg, 85%). ¹H NMR (CDCl₃, 600 MHz) δ 7.60 (d, J=7.2 Hz, 1H), 7.53 (s, 1H), 7.39 (dd, J=7.2, 7.2 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 6.15 (br s, 1H), 5.33 (q, J=7.2 Hz, 1H), 2.99 (d, J=4.8 Hz, 3H), 2.22 (s, 3H), 1.99 (s, 3H), 1.88 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₅H₂₁N₄O (M+H)⁺ 273.1710, found 273.1709.

Step 5. Synthesis of 3-(1-(3,5-Dimethyl-4-(4-(phenoxymethyl)benzamido)-1H-pyrazol-1-yl)ethyl)-N-methylbenzamide (F2)

Compound F2 was prepared from amine IF6a and 4-phenoxylbenzoic acid via an amide formation reaction (HBTU coupling) Yellow oil (50 mg, 40%). ¹H NMR (CDCl₃, 600 MHz) δ 7.91 (d, J=7.7 Hz, 2H), 7.69 (d, J=7.7 Hz, 1H), 7.56 (d, 8.2 Hz, 2H), 7.37 (t, J=7.7 Hz, 1H), 7.33 (s, 1H), 7.32-7.28 (m, 3H), 7.08 (s, 1H), 7.00-6.96 (m, 3H), 6.62-6.57 (m, 1H), 5.42 (q, J=7.0 Hz, 1H), 5.15 (s, 2H), 2.98 (d, J=4.7 Hz, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.95 (d, J=7.0 Hz, 3H). HRMS (ESI⁺) calcd for C₂₉H₃₁N₄O₃ (M+H)⁺ 483.2396, found 483.2383.

Example 74 Synthesis of 3-(1-(3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)ethyl)-N-methylbenzamide (F3)

Compound F3 was prepared from amine IF6a and IE9 via an amide formation reaction (EDC coupling). White solid (30 mg, 53%). ¹H NMR (DMSO-d₆, 600 MHz) δ 9.52 (s, 1H), 8.42 (d, J=4.2 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.54 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.40 (dd, J=7.8, 7.8 Hz, 1H), 7.29 (d, J=6.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 5.31 (s, 2H), 2.77 (d, J=4.2 Hz, 3H), 2.28 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.80 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₃₁H₃₂F₃N₄O₃(M+H)⁺ 565.2427, found 565.2428.

Example 75 Synthesis of 4-(1-(3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)ethyl)-N-methylpicolinamide (F4) Step 1. Synthesis of Ethyl 4-Acetylpicolinate (IF2b)

Aqueous H₂O₂ (30%, 43 mL, 400 mmol) was added dropwise to ethyl pyruvate (72 g, 620 mmol) at 0° C. with stirring. The resulting solution was added dropwise to a mixture of 4-acetylpyridine (IF1, 5.0 g, 40 mmol), concentrated H₂SO₄ (6.3 mL), and FeSO₄.7H₂O (11.5 g, 120 mmol) in CH₂Cl₂ (500 mL)/H₂O (30 mL) at rt over a period of 1 h. After the mixture was allowed to stir for additional 30 min, the organic phase was separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic phase was washed with water, brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford compound IF2b as a white solid (1.10 g, 14%). ¹H NMR (CDCl₃, 600 MHz) δ 8.96 (d, J=4.8 Hz, 1H), 8.54 (s, 1H), 7.93 (dd, J=4.2, 1.8 Hz, 1H), 4.53 (q, J=7.2 Hz, 2H), 2.70 (s, 3H), 1.48 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₀H₁₂NO₃ (M+H)⁺ 194.0812, found 194.0809.

Step 2. Synthesis of Methyl 4-(1-Hydroxyethyl)picolinate (IF3b)

To a solution of compound IF2b (1.10 g, 5.7 mmol) in MeOH (50 mL) was slowly added NaBH₄ (430 mg, 11.4 mmol) and the mixture was allowed to stir at rt for 2 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-80% EtOAc/hexanes) to afford compound IF3b as a white solid (850 mg, 76%). ¹H NMR (CDCl₃, 600 MHz) δ 8.71 (d, J=4.2 Hz, 1H), 8.14 (s, 1H), 7.52 (d, J=4.8 Hz, 1H), 5.00 (q, J=6.6 Hz, 1H), 4.02 (s, 3H), 1.54 (d, J=6.6 Hz, 3H). HRMS (ESI⁺) calcd for C₉H₁₂NO₃ (M+H)⁺ 182.0812, found 182.0815.

Step 3. Synthesis of 4-(1-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)ethyl)-N-methylpicolinamide (IF5b)

To a solution of compound IF3b (850 g, 4.35 mmol), 3,5-dimethyl-4-nitropyrazole (675 mg, 4.79 mmol) and PPh₃ (1.37 g, 5.22 mmol) in THF (40 mL) was slowly added DEAD (1.05 g, 5.22 mmol) and the mixture was allowed to stir at rt for 12 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash column chromatography (0-20% MeOH/CH₂Cl₂) to afford the coupling product as a yellow solid (280 mg, 19%). The resulting methyl ester (280 mg, 0.84 mmol) was dissolved in MeNH₂/EtOH (5 mL) in a sealed tube and heated at 70° C. for 24 h. After the solvent was evaporated in vacuo, the residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IF5b as a white solid (100 mg, 37%). ¹H NMR (CDCl₃, 600 MHz) δ 8.50 (d, J=4.8 Hz, 1H), 8.07 (s, 1H), 8.00 (br s, 1H), 7.13 (d, J=5.4 Hz, 1H), 5.47 (q, J=7.2 Hz, 1H), 3.04 (d, J=5.4 Hz, 3H), 2.56 (s, 3H), 2.54 (s, 3H), 1.94 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₄H₁₈N₅O₃ (M+H)⁺ 304.1404, found 304.1405.

Step 4. Synthesis of 4-(1-(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-methylpicolinamide (IF6b)

To a solution of compound IF5b (100 mg, 0.31 mmol) and NiCl₂.6H₂O (147 mg, 0.62 mmol) in MeOH (20 mL) was slowly added NaBH₄ (50 mg, 1.24 mmol) and the mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH₄Cl (50 mL) and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K₂CO₃, and concentrated in vacuo. The residue was purified by flash column chromatography (0-15% MeOH/CH₂Cl₂) to afford compound IF6b as a brown oil (60 mg, 70%). ¹H NMR (CDCl₃, 600 MHz) δ 8.40 (d, J=4.8 Hz, 1H), 8.03-7.95 (m, 2H), 6.93 (d, J=5.4 Hz, 1H), 5.33 (q, J=7.2 Hz, 1H), 3.03 (d, J=5.4 Hz, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.90 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₁₄H₂₀N₅O (M+H)⁺ 274.1662, found 274.1668.

Step 5. Synthesis of 4-(1-(3,5-Dimethyl-4-(4-((2-methyl-4-(trifluoromethyl)phenoxy)methyl)benzamido)-1H-pyrazol-1-yl)ethyl)-N-methylpicolinamide (F4)

Compound F4 was prepared from amine IF6b and IE9 via an amide formation reaction (EDC coupling). White solid (15 mg, 13%). ¹H NMR (CDCl₃, 600 MHz) δ 8.45 (d, J=4.8 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.04-8.00 (m, 1H), 7.98 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.58-7.52 (m, 2H), 7.44-7.39 (m, 2H), 7.10 (dd, J=4.8, 1.8 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 5.41 (q, J=7.2 Hz, 1H), 5.21 (s, 2H), 3.03 (d, J=5.4 Hz, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.95 (d, J=7.2 Hz, 3H). HRMS (ESI⁺) calcd for C₃₀H₃₁F₃N₅O₃(M+H)⁺566.2374, found 566.2375.

Example 76 Synthesis of 3-((3,5-Dimethyl-4-(4-((pyridin-2-yloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (G1)

Compound G1 was prepared from intermediate IA12 via a displacement reaction in a fashion similar to the one described for compound D1. Colorless semi solid, 6.0 mg, 1% yield. ¹H NMR (CDCl₃, 600 MHz) δ 7.89 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.41-7.32 (m, 4H), 7.30 (d, J=6.6 Hz, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 6.69 (s, 1H), 6.60 (d, J=9.0 Hz, 1H), 6.20 (dd, J=6.9, 6.9 Hz, 1H), 5.26 (s, 2H), 5.20 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.16 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₈N₅O₃ (M+H)⁺470.2192, found 470.2194.

Example 77 Synthesis of 3-((3,5-Dimethyl-4-(4-((pyridin-3-yloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (G2)

Compound G2 was prepared from intermediate IA12 via a displacement reaction in a fashion similar to the one described for compound D1. White solid, 13 mg, 38% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.28 (d, J=1.8 Hz, 1H), 8.25 (d, J=3.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.37 (d, J=7.5, 7.5 Hz, 1H), 7.26-7.32 (m, 3H), 7.18 (s, 1H), 6.74-6.68 (m, 1H), 5.25 (s, 2H), 5.20 (s, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.17 (s, 3H), 2.05 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₈N₅O₃ (M+H)⁺470.2192, found 470.2196.

Example 78 Synthesis of 3-((3,5-Dimethyl-4-(4-((pyridin-4-yloxy)methyl)benzamido)-1H-pyrazol-1-yl)methyl)-N-methylbenzamide (G3)

Compound G3 was prepared from intermediate IA12 via a displacement reaction in a fashion similar to the one described for compound D1. White solid, 6 mg, 17% yield. ¹H NMR (CDCl₃, 600 MHz) δ 8.45 (d, J=5.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.44 (s, 1H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.29-7.26 (m, 1H), 7.18 (s, 1H), 7.88 (d, J=6.0 Hz, 2H), 6.61-6.55 (m, 1H), 5.28 (s, 2H), 5.20 (s, 2H), 2.99 (d, J=4.8 Hz, 3H), 2.20 (s, 3H), 2.07 (s, 3H). HRMS (ESI⁺) calcd for C₂₇H₂₈N₅O₃ (M+H)⁺470.2192, found 470.2195.

Example 79 Cell Viability Assay

MIA PaCa-2 cells (CRL-1420, ATCC) were maintained in DMEM media supplemented with 10% FBS, 2.5% HS, 1% GlutaMAX, 1% sodium pyruvate, 100 U/mL penicillin, and 100 μg/mL streptomycin. Cell culture media and additives were purchased from Gibco. Cells were plated in 96-well plates at |1−2.5|×10⁴ cells per well in the DMEM growth media. One microliter of a 2-fold serially diluted compound solution in DMSO (Sigma) starting at 20 mM (100 μM final concentration) was added to each well. The final volume in each well was 200 μL, yielding a final DMSO concentration of 0.5%. Control wells contained 0.5% DMSO (100% viability) or 25% DMSO (background) and all reactions were done in triplicate. The plate was incubated for 72 h at 37° C. in a 5% CO₂/95% air humidified atmosphere.

Measurement of cell viability was carried out using a modified method of Mosmann based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma). MTT solution was prepared fresh at 1 mg/mL in serum-free and phenol red-free RPMI 1640 media. After 200 μL of MTT solution was added to each well, the plate was incubated as described above for 3 h. The MTT solution was removed, and the formazan crystals were solubilized with 200 μL of isopropanol. The plate was read on a SpectraMax i3 spectrophotometer (Molecular Devices) at 570 nm for formazan and 650 nm for background subtraction. EC₅₀ values were calculated by fitting the data in GraphPad Prism software. EC₅₀ values were determined in triplicate. Results are demonstrated in Tables 1-9.

TABLE 1 Antiproliferative activity.

EC₅₀ MIA PaCa-2 Compound R¹ R² R³ (μM) A1  H H H 10 A2a C(O)NH₂ H H >100 A2b H C(O)NH₂ H 9.2 A2c H H C(O)NH₂ 42 A3a C(O)NHMe H H 12 A3b H C(O)NHMe H 6.2 A3c H H C(O)NHMe 7.7 A4a H C(O)N(Me)₂ H 6.4 A4b H C(O)NHEt H 11 A4c H C(O)NH^(i)Pr H 8.9 A4d H C(O)NHPh H 6.4 A5a NO₂ H H 7.8 A5b H NO₂ H 11 A5c H H NO₂ 6.0 A6a NH₂ H H >100 A6b H NH₂ H 35 A6c H H NH₂ 11 A7a NHC(O)Me H H 50 A7b H NHC(O)Me H 2.7 A7c H H NHC(O)Me 2.6

TABLE 2 Antiproliferative activity.

EC₅₀ MIA PaCa-2 Compound X—Y (μM) B1

17 B2

6.1 B3

25

TABLE 3 Antiproliferative activity.

  C1-C5, C7

  C6 EC₅₀ MIA PaCa-2 Compound R (μM) C1

8.3 C2

17 C3

5.4 C4

69 C5

8.2 C6 NA 32 C7

14 NA, not applicable.

TABLE 4 Antiproliferative activity.

EC₅₀ MIA PaCa-2 Compound R (μM) D1

9.1 D2

6.0

TABLE 5 Antiproliferative activity.

  D3a-D10

  D11-D12 EC₅₀ (MIA PaCa-2) Compound R¹ R² R³ (μM) D3a Me H H 2.1 D3b H Me H 6.2 D3c H H Me 2.6 D4a OMe H H 8.5 D4b H OMe H 6.2 D4c H H OMe 8.0 D5a Cl H H 6.3 D5b H Cl H 5.9 D5c H H Cl 4.2 D6a F H H 5.6 D6b H F H 7.7 D6c H H F 3.1 D7a CN H H 12 D7b H CN H 10 D7c H H CN 5.6 D8a NO₂ H H 11 D8b H NO₂ H 10 D8c H H NO₂ 9.7 D9a CF₃ H H 10 D9b H CF₃ H 2.3 D9c H H CF₃ 0.80 D10 Me H CF₃ 0.62 D11 H H CF₃ 0.87 D12 Me H CF₃ 1.1

TABLE 6 Antiproliferative activity.

  E1a-E4b

  E5a-b MIA PaCa-2 EC₅₀ Compound R¹ R² (μM) E1a

H 0.48 E1b

Me 6.3 E2a

H 0.85 E2b

Me 0.33 E3a

H 8.6 E3b

Me 7.6 E4a

H 13 E4b

Me 4.9 E5a

Me 6.7 E5b

Me 9.4

TABLE 7 Antiproliferative activity.

MIA PaCa-2 EC₅₀ Compound R¹ R² R³ (μM) E6a

H H 8.4 E6b

CF₃ H 4.6 E6c

CF₃ Me 1.2 E7a

CF₃ H 8.1 E7b

CF₃ Me 10  

TABLE 8 Antiproliferative activity.

MIA PaCa-2 Com- EC₅₀ pound R¹ R² R³ R⁴ (μM) F1

H H Me 22 F2

H H H 7.7 F3

CF₃ Me H 2.4 F4

CF₃ Me H 4.0

TABLE 9 Antiproliferative activity.

MIA PaCa-2 EC₅₀ Compound R (μM) G1

>100 G2

   24 G3

   99

Example 80 Cell Viability Assay in Panc-1 Cells

Panc-1 cells are maintained in RPMI 1640 (Invitrogen 11875) media supplemented with 10% FBS, 1% Penicillin/Streptomycin and 1% Glutamax-1. Cells were plated in 96-well plates at 25×10⁴ cells/ml. After 24 hours, compounds were added at 9, 3× dilutions in triplicate from 100 uM final concentration in the appropriate growth media. Plates were incubated for 72 hours at 37° C. in a 5% CO₂/95% air humidified atmosphere after which time the media was removed and MTT was added in RPMI phenol red free media. The MTT was removed after 3 hours and formazan crystals were solubilized with 200 μL of isopropanol. Plates were read on a Molecular Devices SpectraMax i3 spectrophotometer at 570 nm for formazan and 690 nm for background subtraction. EC50 values were calculated by fitting the data in GraphPad Prism software. Data for representative compounds is provided in Table 10.

TABLE 10 Antiproliferative activity. Compound Panc-1 EC₅₀ (μM) A1 9.0 A2a >100 A2b 11 A2c >100 A3a 36 A3b 5.2 A3c 14 A4a 1.2 A4b 1.6 A4c 1.4 A5a 23 A5b 20 A5c 5.3 A6a 44 A6b 9.7 A6c 22 A7a >100 A7b 12 A7c 31 C3 0.76 C4 51 C5 6.0 D2 1.3 D3a 0.61 D3b 0.56 D3c 13 D4a 25 D4b 6.2 D4c 48 D5a 9.9 D5b 0.038 D5c 2.0 D6a 3.0 D6b 0.21 D6c 6.9 D7a 8.5 D7c 22 D9a 0.44 D9b 0.76 D9c 0.21

Example 81 Cell Viability Assay in MCF10A Cells (Normal Human Mammary Cells)

MCF10A cells are maintained in minimum essential medium (MEM) (Invitrogen 11095) supplemented with 10% FBS (Invitrogen 16000), 1% 10× non-essential amino acids (NEAA) (Invitrogen 11140), 1% Penicillin/Streptomycin (Invitrogen 15140), 1% GlutaMAX (Invitrogen 35050-061), 20 ng/mL EGF, 0.5 mg/mL hydrocortisone, 100 ng/mL cholera toxin, 10 μg/mL insulin.

Cells were plated in 96-well plates at 25×10⁴ cells/ml. After 24 hours, compounds were added at 9, 3× dilutions in triplicate from 100 uM final concentration in the appropriate growth media. Plates were incubated for 72 hours at 37° C. in a 5% CO₂/95% air humidified atmosphere after which time the media was removed and MTT was added in RPMI phenol red free media. The MTT was removed after 3 hours and formazan crystals were solubilized with 200 μL of isopropanol. Plates were read on a Molecular Devices SpectraMax i3 spectrophotometer at 570 nm for formazan and 690 nm for background subtraction. EC50 values were calculated by fitting the data in GraphPad Prism software. Data for representative compounds is provided in Table 11.

TABLE 11 Antiproliferative activity. Compound MCF10A EC₅₀ (μM) D9c 6.7 D10 4.8 D11 8.6 D12 6.6 E1a 7.8 E2a 8.3 E2b 7.4

Example 82 In Vitro ADME Evaluation

Plasma Stability Assay

The plasma stability assay was performed in triplicate by incubating a compound in normal mouse and human plasma at 37° C. At 0, 1, 3, 6, and 24 h, aliquots of the plasma mixture were taken and quenched with 3 volumes of acetonitrile containing an appropriate internal standard. The samples were then vortexed and centrifuged at 14,000 rpm for 5 min. The supernatants were collected and analyzed by LC-MS/MS to determine the remaining percentage at various time points. Data for representative compounds is provided in Table 12.

Microsomal Stability Assay

The in vitro microsomal stability assay was conducted in triplicate in mouse and human liver microsomal systems. In a typical incubation, a compound (typically 1 μM final concentration) was spiked into the reaction mixture containing 0.5 mg/mL of liver microsomal protein and 1 mM of NADPH in 0.1 M potassium phosphate buffer (pH 7.4) at 37° C. At various time points, 1 volume of reaction aliquot was taken and quenched with 3 volumes of acetonitrile with an appropriate internal standard. The samples were then vortexed and centrifuged at 14,000 rpm for 5 min. The supernatants were collected and analyzed by LC-MS/MS to determine the in vitro metabolic half-life (t_(1/2)) and intrinsic clearance (CL_(int)). Verapamil was used as a positive control. Data for representative compounds is provided in Table 12.

LC-MS/MS Bioanalysis

Quantification and analysis of compounds in biological samples were carried out on an AB Sciex QTrap 5500 mass spectrometer coupled with an Agilent 1260 Infinity HPLC. The chromatographic separation of compounds was achieved using a Phenomenex Kinetex C18 column (50×2.1 mm, 2.6 μm), and MS/MS analysis was conducted using an ESI ion source with MRM detection. The MS/MS detection parameters including declustering potential (DP), entrance potential (EP), collision energy (CE), and collision cell exit potential (CXP) were optimized for each compound.

Thermodynamic Solubility Assay

The aqueous solubility of a test compound was determined in DPBS (pH=7.4) under thermodynamic solubility conditions. Briefly, a saturated solution was made by adding DPBS to the solid compound. The mixture was shaken at 200 rpm for 48 h in a MaxQ 6000 orbital shaker at ambient temperature to allow equilibrium between the solid and dissolved compound. The suspension was then filtered through a 0.45 μm PVDF syringe filter and the filtrate was collected for analysis using UV spectrometry (SpectraMax M5e, Molecular Devices) at λ=240 nm. Data for representative compounds is provided in Table 12.

TABLE 12 In Vitro ADME Properties of Selected Compounds.^(a) Plasma Stability Microsomal Stability Aqueous Com- (% remaining, 6 h/24 h) t_(1/2) (min) Solubility pound Mouse Human Mouse Human (μM) D9c 91/77  99/100 60 34  67.3 ± 5.2 D10 88/93  98/100 53 53 166 ± 2 D11 2.1/0.1 96/94 7.4 8.3 D12 1.6/0.1 92/95 9.7 14 E1a —/99  —/100 65 47 E1b —/96  —/100 75 47 E2a —/91 —/98 64 112 E2b —/84  —/100 89 89 211 ± 5 E3a  —/100 —/94 144 82 E3b  —/100 —/98 139 74 E4a —/98 —/97 151 65 E4b —/99 —/98 126 57 ^(a)Plasma and microsomal stabilities as well as aqueous solubility were determined in triplicate.

Example 83 Caco-2 Permeability Assay

Cell Culture. The human colon adenocarcinoma cell line Caco-2 was purchased from ATCC (American Type Culture Collection, Manassas, Va.), and was cultured in a humidified atmosphere of 5% CO2 at 37° C. Caco-2 cells were cultured in DMEM with 10% FBS, 1% NEAA, 1% GlutaMax and 1% penicillin and streptomycin solution. The culture medium was changed every other day during cell growth and differentiation. On achieving 80-90% confluence, the cells were rinsed with pre-warm DPBS (pH 7.4) and split using trypsin. The cells were then seeded on membranes of Millipore Millicell-24 cell culture device. The transepithelial electrical resistance (TEER) were assessed to reflect membrane integrity using a Millicells® ERS-2 (Millipore, USA). The Caco-2 cell monolayers were used for transport experiments on day 21 post-seeding with TEER values >500 Ω·cm2. Bidirectional Transport Experiments. Before the transport experiments, the cell monolayer was washed three times with HBSS. Then, the plates were incubated in fresh permeability assay buffer (HBSS containing 10 mM glucose and 20 mM HEPES, pH 7.4) at 37° C. The experiments were conducted by spiking test compounds to either the apical (AP, 0.4 mL) or basolateral side (BL, 0.8 mL), while the receiving chamber contained the corresponding volume of pre-warmed permeability assay buffer. Every experiment was repeated in duplicate, and the plates were incubated in an orbital shaker at 37° C., 50 rpm/min. To assess the drug transport, at the incubation time of 20, 40, 60 and 80 min, aliquot was removed and was immediately replenished with an equal volume of permeability assay buffer. The samples were then subjected to LC/MS/MS analysis. The apparent permeability coefficient was indicated by the absorption rate constant Papp. It could be calculated as PBA (measured in BL to AP direction) or PAB (measured in AP to BL direction), using the equation of Papp=(dQ/dt)/(A×C0). dQ/dt is the rate at which the compound appears in the receiver chamber (nmol/s), A is the surface area of the filter membrane (0.7 cm2) and C0 is the initial concentration in the donor chamber (μM). Efflux ratio (ER) was calculated by the equation of ER=PBA/PAB, where PBA is the Papp value measured in BL to AP direction, and PAB is the Papp value measured in AP to BL direction. Data for representative compounds is provided in Table 13.

TABLE 13 Caco-2 Permeability. Caco-2 P_(app) (×10⁻⁶ cm/sec) Compound A to B B to A D9c 8.26 19.3 D10 3.72 11.2 E1a 24.5 21.0 E1b 3.58 7.17 E2a 5.02 5.69 E2b 8.34 5.96

Example 84

The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I (compound X), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0

(iii) Capsule mg/capsule Compound X= 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. 

What is claimed is:
 1. A compound of formula I:

wherein: ring A is aryl; ring B is aryl, heteroaryl, carbocycle or heterocycle; L¹ is —NHC(O)—* or -L^(A)-NR¹SO₂-L^(B)-, wherein each R¹ is hydrogen; each L^(A) is absent; each L^(B) is absent, wherein * indicates the point of attachment to A; L² is C₁₋₄ alkylene, -L^(C)-O-L^(D)-, -L^(C)-S-L^(D), -L^(C)-NR²-L^(D)-, -L^(C)-NR²C(O)-L^(D)-, or -L^(C)-C(O)NR²-L^(D)-; wherein each R² is independently hydrogen or C₁₋₄ alkyl; each L^(C) is independently absent or C₁₋₄ alkylene; each L^(D) is independently absent or C₁₋₄ alkylene; L³ is C₁₋₄ alkylene,; X is N; Y is N; Z is C—R^(Z); wherein R^(Z) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁵, —SR⁵, —N(R⁵)₂, —NO₂ or —CN; wherein each R⁵ is independently hydrogen or C₁₋₄ alkyl; E is C—R^(E); wherein R^(E) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁶, —SR⁶, —N(R⁶)₂, —NO₂ or —CN; wherein each R⁶ is independently hydrogen or C₁₋₄ alkyl; each R^(A) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁷, —SR⁷, —N(R⁷)₂, —NO₂ or —CN; wherein each R⁷ is independently hydrogen or C₁₋₄ alkyl; each R^(B) is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, —OR⁸, —SR⁸, —N(R⁸)₂, —NO₂ or —CN; wherein each R⁸ is independently hydrogen or C₁₋₄ alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and the group

 is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 2. The compound or salt of claim 1, wherein R^(Z) is C₁₋₄ alkyl.
 3. The compound or salt of claim 1, wherein R^(E) is C₁₋₄ alkyl.
 4. The compound or salt of claim 1, wherein ring B is phenyl, pyridyl, cyclohexyl or naphthalenyl.
 5. The compound or salt of claim 1, wherein the group

is selected from the group consisting of:


6. The compound or salt of claim 1, wherein L¹ is —NHC(O)—*.
 7. The compound or salt of claim 1, wherein L² is —CH₂O—.
 8. The compound of claim 1, wherein L³ is —CH₂— or —CH(CH₃)—.
 9. The compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceutical composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 11. The compound:

or a pharmaceutically acceptable salt thereof.
 12. The compound or salt of claim 1, wherein the group

is


13. The compound or salt of claim 1, wherein the group

is


14. A pharmaceutical composition comprising a compound as described in claim 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 